Skip to main content
  • ASM
    • Antimicrobial Agents and Chemotherapy
    • Applied and Environmental Microbiology
    • Clinical Microbiology Reviews
    • Clinical and Vaccine Immunology
    • EcoSal Plus
    • Eukaryotic Cell
    • Infection and Immunity
    • Journal of Bacteriology
    • Journal of Clinical Microbiology
    • Journal of Microbiology & Biology Education
    • Journal of Virology
    • mBio
    • Microbiology and Molecular Biology Reviews
    • Microbiology Resource Announcements
    • Microbiology Spectrum
    • Molecular and Cellular Biology
    • mSphere
    • mSystems
  • Log in
  • My alerts
  • My Cart

Main menu

  • Home
  • Articles
    • Current Issue
    • Accepted Manuscripts
    • Archive
    • Minireviews
  • For Authors
    • Submit a Manuscript
    • Scope
    • Editorial Policy
    • Submission, Review, & Publication Processes
    • Organization and Format
    • Errata, Author Corrections, Retractions
    • Illustrations and Tables
    • Nomenclature
    • Abbreviations and Conventions
    • Publication Fees
    • Ethics Resources and Policies
  • About the Journal
    • About IAI
    • Editor in Chief
    • Editorial Board
    • For Reviewers
    • For the Media
    • For Librarians
    • For Advertisers
    • Alerts
    • RSS
    • FAQ
  • Subscribe
    • Members
    • Institutions
  • ASM
    • Antimicrobial Agents and Chemotherapy
    • Applied and Environmental Microbiology
    • Clinical Microbiology Reviews
    • Clinical and Vaccine Immunology
    • EcoSal Plus
    • Eukaryotic Cell
    • Infection and Immunity
    • Journal of Bacteriology
    • Journal of Clinical Microbiology
    • Journal of Microbiology & Biology Education
    • Journal of Virology
    • mBio
    • Microbiology and Molecular Biology Reviews
    • Microbiology Resource Announcements
    • Microbiology Spectrum
    • Molecular and Cellular Biology
    • mSphere
    • mSystems

User menu

  • Log in
  • My alerts
  • My Cart

Search

  • Advanced search
Infection and Immunity
publisher-logosite-logo

Advanced Search

  • Home
  • Articles
    • Current Issue
    • Accepted Manuscripts
    • Archive
    • Minireviews
  • For Authors
    • Submit a Manuscript
    • Scope
    • Editorial Policy
    • Submission, Review, & Publication Processes
    • Organization and Format
    • Errata, Author Corrections, Retractions
    • Illustrations and Tables
    • Nomenclature
    • Abbreviations and Conventions
    • Publication Fees
    • Ethics Resources and Policies
  • About the Journal
    • About IAI
    • Editor in Chief
    • Editorial Board
    • For Reviewers
    • For the Media
    • For Librarians
    • For Advertisers
    • Alerts
    • RSS
    • FAQ
  • Subscribe
    • Members
    • Institutions
Minireview | Spotlight

Waging War against Uropathogenic Escherichia coli: Winning Back the Urinary Tract

Kelsey E. Sivick, Harry L. T. Mobley
Kelsey E. Sivick
Department of Microbiology and Immunology, University of Michigan Medical School, Ann Arbor, Michigan 48109
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Harry L. T. Mobley
Department of Microbiology and Immunology, University of Michigan Medical School, Ann Arbor, Michigan 48109
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
  • For correspondence: hmobley@umich.edu
DOI: 10.1128/IAI.01000-09
  • Article
  • Figures & Data
  • Info & Metrics
  • PDF
Loading

ABSTRACT

Urinary tract infection (UTI) caused by uropathogenic Escherichia coli (UPEC) is a substantial economic and societal burden—a formidable public health issue. Symptomatic UTI causes significant discomfort in infected patients, results in lost productivity, predisposes individuals to more serious infections, and usually necessitates antibiotic therapy. There is no licensed vaccine available for prevention of UTI in humans in the United States, likely due to the challenge of targeting a relatively heterogeneous group of pathogenic strains in a unique physiological niche. Despite significant advances in the understanding of UPEC biology, mechanistic details regarding the host response to UTI and full comprehension of genetic loci that influence susceptibility require additional work. Currently, there is an appreciation for the role of classic innate immune responses—from pattern receptor recognition to recruitment of phagocytic cells—that occur during UPEC-mediated UTI. There is, however, a clear disconnect regarding how factors involved in the innate immune response to UPEC stimulate acquired immunity that facilitates enhanced clearance upon reinfection. Unraveling the molecular details of this process is vital in the development of a successful vaccine for prevention of human UTI. Here, we survey the current understanding of host responses to UPEC-mediated UTI with an eye on molecular and cellular factors whose activity may be harnessed by a vaccine that stimulates lasting and sterilizing immunity.

MISSION: ERADICATE UPEC-MEDIATED UTI

Urinary tract infection (UTI) is one of the most common infections in humans. Bacteria present in fecal matter inoculate the periurethral area, then the bladder (124, 176, 291), causing symptoms clinically termed cystitis. Left untreated, bacteria ascend the ureters to the kidney and establish a secondary infection, acute pyelonephritis. At this juncture, there is risk of permanent renal scarring, and bacteria can access the bloodstream (282). It is estimated that 40% of women and 12% of men will experience a symptomatic UTI, with incidences peaking in their early 20s or after age 85, respectively (75, 185). Approximately 25% of these women will experience recurrence within 6 to 12 months (75, 185). Uropathogenic Escherichia coli (UPEC) is the most common etiological agent responsible for uncomplicated UTI (93, 94, 282). Uropathogenic strains are classified as extraintestinal pathogenic E. coli, a broad grouping of E. coli that cause diseases other than gastroenteritis and typically lack a type III secretion system (171, 220, 221, 283, 284). Nonetheless, UPEC strains express an assortment of virulence and fitness factors that aid in successful colonization of the mammalian urinary tract (126, 136). In the United States alone, the estimated annual societal cost of UTI is more than 3 billion dollars (159).

Despite a relatively in-depth knowledge base for UPEC physiology and virulence mechanisms (reviewed in references 54, 126, 136, and 284), no licensed vaccine to prevent UTI exists in the United States. A more thorough understanding of the mechanisms involved in the natural immune response to UTI, however, may direct a new approach to harness these responses in a vaccination setting. In this review, current and potential treatments for UPEC-mediated UTI will be surveyed, as well as efforts to identify suitable vaccine candidates. Factors involved in host responses to UTI (summarized in Table 1) and the mechanisms by which UPEC stimulates and influences these responses will also be covered. Lastly, commentary on the steps needed to better understand infection and immunity in the urinary tract and to develop a vaccine that elicits heterologous protective immunity against UPEC is given.

View this table:
  • View inline
  • View popup
TABLE 1.

Summary of mammalian factors associated with the host response to UPEC-mediated UTI

TERRAIN: THE URINARY TRACT

The urinary tract is an impermeable barrier that undergoes continuous expansion and contraction (9). These fluctuations are achieved on a gross level by unfolding of the mucosal surface and on a molecular level by cellular membrane dynamics. Specialized fusiform vesicles are thought to be endo- and exocytosed at a rate that provides additional membrane surface area during expansion (9). This unique mucosa is a transitional epithelium with large, highly differentiated, multinuclear superficial facet (umbrella) cells lining the luminal surface (Fig. 1A and B) (9). The apical side of the umbrella cells consists of a detergent-insoluble membrane containing a family of integral membrane proteins termed uroplakins (9). Uroplakins are partly responsible for the barrier function of the uroepithelium and act as receptors for FimH, the tip adhesin of UPEC type 1 fimbriae (298). For the purposes of this review, “postinoculation” and “infection” refer to E. coli accessing the urinary tract by the transurethral route, either experimentally in animals and volunteers or naturally in patients.

FIG. 1.
  • Open in new tab
  • Download powerpoint
FIG. 1.

Histological and schematic views of the murine bladder. (A) Hematoxylin and eosin (H&E)-stained section from a healthy wild-type C57BL/6 female mouse. Magnification, ×200. Scale bar, 100 μm. (B) Schematic representation of bladder physiology shown in panel A. Umbrella cells line the luminal surface of the transitional epithelium. The basal side of the umbrella cell layer consists of intermediate and basal cells, followed by the lamina propria, the primary site of edema and inflammation during UTI. (C and D) H&E-stained sections from wild-type C57BL/6 mice that were either left untreated (C) or infected for 48 h (D). Note the severe inflammation and edema in the lamina propria of the infected animal. Magnification, ×40. Scale bar, 500 μm.

WEAPONS SYSTEMS: CURRENT AND PROPOSED TREATMENTS AND VACCINE INITIATIVES FOR UTI

There are several practiced and proposed therapeutics for UTI management. Prophylactic treatments include estrogen in postmenopausal women (36, 41, 125, 140, 198, 208, 214) or cranberry juice (13, 77, 200), although the efficacy of the former remains controversial. Treatment of UPEC-infected mice with forskolin, a drug that increases intracellular cyclic AMP (cAMP) levels, expels UPEC from intracellular vesicles into the extracellular milieu, rendering the bacteria susceptible to immune responses and antibiotics (29). Similarly, exposing the bladder to protamine sulfate, a highly cationic protein, removes bound and intracellular UPEC by causing umbrella cells to exfoliate (179), unfortunately with a significant level of discomfort, as reported by study volunteers (158). In addition to a number of nonspecific chemical treatments (274), both small-molecule inhibitors (33) and specific antibody directed against FimH (256) demonstrated some utility in preventing bacterial adherence. While antibiotic therapy remains the standard treatment for UTI, overuse leads to deleterious alterations of the normal host microbiota (52) and selection for resistant strains (50, 76, 93, 94, 128, 178), prompting the need for vaccine-mediated prevention of UTI.

Early vaccine studies focused on the lipopolysaccharide (LPS) side chain (O) antigen (Table 2) (275). There are trends regarding the frequencies of particular O antigens among UTI isolates (68, 249, 284), and O-antigen-specific antibodies demonstrate an antiadhesive effect (249). Nonetheless, significant structural heterogeneity may represent an insurmountable obstacle for development of an O-antigen-based vaccine. Furthermore, a study evaluating antibody responses in mice intranasally vaccinated with a killed E. coli lacking capsule and O antigen demonstrated that these surface features actually obstruct optimal humoral responses (219).

View this table:
  • View inline
  • View popup
TABLE 2.

Previously tested vaccines for UPEC-mediated UTI.

Later studies involved vaccines directed against particular virulence factors (Table 2). P fimbriae are adherence organelles that play a role in kidney colonization in mice and humans (187, 188, 288, 297); the pore-forming toxin alpha-hemolysin (HlyA) and P fimbriae are proposed minimal factors required for colonization of and dissemination from the kidney (186). There are convincing data using both murine (186, 187, 231) and primate models (216, 217) that vaccination against P fimbriae or HlyA prevents renal colonization and damage. Additionally, to overcome P fimbrial allelic variability, linear peptide sequences that generated cross-reactive antibodies were evaluated as protective antigens (191, 231). Despite these successes, vaccines targeting P fimbriae may not be effective because of their limited role during bladder colonization. Type 1 fimbria is a bona fide virulence factor of UPEC and, in contrast to P fimbria, is critical for bladder colonization (11, 48, 92, 256). Animals vaccinated with various components of type 1 fimbriae had increased levels of antigen-specific antibodies and decreased levels of colonization upon challenge (153, 154, 194, 204, 256). Unfortunately, expression of type 1 fimbria is subject to phase variation, allowing UPEC to evade humoral responses targeting this organelle (59, 240). Additionally, since nonpathogenic isolates also express type 1 fimbriae (97, 126), targeting this population may result in detrimental disruption of the host microbiota. Also of note, both P and type 1 fimbriae were not necessary for colonization of the human neurogenic bladder, indicating the need for alternative targets in certain high-risk patient groups (118).

Iron is essential for nearly all organisms (83, 295), and UPEC strains encode a battery of genes involved in iron acquisition. Vaccination with UPEC outer membrane protein (OMP) fractions enriched for iron receptors protects against experimental sepsis (32, 57). Additionally, mice vaccinated subcutaneously with denatured IroN, an OMP siderophore receptor and urovirulence factor (222), had both increased levels of antigen-specific serum IgG and reduced kidney colonization upon challenge (Table 2) (223). Undetectable levels of IgA in the bladder mucosa after this vaccination may explain why these animals were not protected from cystitis (223). Recently, a broad functional vaccinology initiative was conducted using an “omics” approach to identify PASivE vaccine candidates: UPEC proteins that are pathogen-specific, antigenic, surface-exposed, and invivoexpressed (5, 238). Strikingly, the top targets identified by this approach were all OMPs functioning in iron uptake. Intranasal vaccination with three of six candidates afforded protection from cystitis and pyelonephritis (5), suggesting that combining antigenic motifs found in these proteins may be an effective multivalent vaccine for UTI.

Vaccines consisting of bacterial components or whole cells have also been assessed (Table 2). Transurethral immunization of mice with a live-attenuated UPEC strain lacking the ability to persist in the urinary tract engendered heterologous protection (27), a potential platform for further development. On the complex vaccine front, Uro-Vaxom is a daily oral capsule containing a lyophilized mix of membrane proteins from 18 E. coli strains (95, 253). The formulation elicits a number of immunological effects in vitro (230, 278, 289, 290), generates specific antibodies in mice and humans (15, 51, 117, 233), and generally reduces the incidence of UTI in patients (22, 51, 95, 156, 160, 232, 253). Unfortunately, complications can occur due to toxicity, and the necessity of daily administration presents supply and compliance issues. SolcoUrovac, a vaginal suppository containing 10 heat-killed uropathogenic strains, has been tested in mice (146, 272), in nonhuman primates (270), and in clinical trials (91, 112, 114, 224, 266-269). While safe, SolcoUrovac vaccination did not result in appreciable increases in local specific antibody (267, 269, 270), nor did it afford protection without periodic readministration (267, 269).

TACTICAL DEFENSIVE MANEUVERS: HOST FACTORS TO PREVENT UPEC COLONIZATION

Uroepithelial adherence is critical for establishment of UTI (284). UPEC strains possess an impressive repertoire of adhesins that enable them to aggregate and adhere to cellular surfaces (107, 137, 203, 235, 276). Consequently, the first line of host defense against UTI is concentrated on preventing UPEC adherence to the bladder mucosa. The luminal surface of the bladder is lined with highly sulfated and anionic glycosaminoglycans (GAGs) that contribute to bladder wall impermeability and afford an antimicrobial antiadherence property (120, 158, 196, 197, 199, 237). Intuitively, urine flow seems to be a convenient defense mechanism; however, FimH binds to mannose moieties using “catch-bonds,” interactions that are actually strengthened by the sheer stress induced during urine flow (257). Thus, more active mechanisms, like umbrella cell exfoliation (10, 60, 81, 166, 176, 177, 189), remove adherent UPEC. Exfoliation occurs by an apoptosis-like mechanism that is promoted by FimH (142, 176). FimH induces cellular events consistent with activation of both extrinsic (death receptor) and intrinsic (mitochondrial) apoptotic pathways, with cross talk between the two signaling cascades mediated by the proapoptotic Bid protein (141). UPEC-induced urothelial cell death correlates with increased bladder cell differentiation and is also dependent on expression of the uroplakin IIIa receptor, a terminal differentiation marker (180, 258). Nuclear factor of kappa light chain polypeptide gene enhancer in B cells (NF-κB) is a transcription factor known for induction of proinflammatory genes concomitant with antiapoptotic genetic programs (20, 280). UPEC, independent of type 1 fimbriae, is able to suppress NF-κB and thereby promotes host cell apoptosis (142). Given the role for apoptotic cell exfoliation in UPEC host defense, promoting this sloughing activity may appear counter-productive for the bacteria. Nonetheless, cellular apoptosis may be an acceptable side effect of inhibiting the proinflammatory gene expression and ensuing cellular responses also initiated by NF-κB.

Tamm-Horsfall protein (THP) was first described in the early 1950s as a high-molecular-weight protein present in human urine (252); its ability to bind E. coli fimbriae was not recognized until some 30 years later (190, 192, 195). A detailed biochemical analysis revealed that soluble THP from both mouse and human urine was able to bind type 1 fimbriae by virtue of its mannose moieties, inhibiting fimbrial interaction with uroplakin receptors (172, 193). This phenotype translated in vivo as thp−/− mice were unable to control lower-UTI (21). THP also appears to act as an innate-adaptive immunoregulatory molecule that can activate dendritic cells (225).

BATTLEFIELD INTELLIGENCE: HOST SIGNALING IN RESPONSE TO UPEC RECOGNITION

Upon successful adherence to the uroepithelium, Toll-like receptor (TLR) recognition of pathogen-associated molecular patterns (123, 164) generates signaling cascades to control infection and direct adaptive responses (55, 242). It has been known for over 2 decades that C3H/HeJ mice, harboring a mutation in the Toll/interleukin-1 receptor (TIR) domain of TLR4 (206), cannot resolve UTI as efficiently as LPS-responsive C3H/HeN counterparts (250). In accordance, tlr4−/− mice had significantly higher bacterial burdens in their bladders than similarly infected wild-type mice (12). This clearance defect is the result of insufficient downstream cytokine and chemokine production and neutrophil recruitment (96, 111, 201, 236). Data from mouse chimeras disclosed that TLR4 on both stromal and hematopoietic cells is critical for normal inflammatory responses and clearance of UPEC in the bladder (227) and kidney (201). Correspondingly, children with low TLR4 expression on their neutrophils display an asymptomatic bacteriuria (ABU) carrier state lacking both inflammation and bacterial clearance (211). A similar response is exhibited by C3N/HeJ mice following UPEC inoculation (210).

TLR4-mediated signaling in the urinary tract does not appear to be the result of the archetypal interaction with LPS. Both the role of LPS in and the molecular trigger of TLR4 signaling by UPEC are topics of debate (14, 106, 228). Studies using the A498 human kidney cell line indicate that TLR4 signaling in response to UPEC requires P fimbriae and can be mediated independently of LPS (79, 104, 106). Mechanistic details regarding this phenomenon include P fimbriae binding to surface glycosphingolipids (GSLs) and subsequent release of the GSL membrane-anchoring domain, ceramide (72). Ceramide appears to act as a TLR4 agonist and the putative intermediate for TLR4 signaling initiated by P fimbriae (72). In contrast to LPS-independent signaling by P fimbriae, there appears to be a cooperative stimulation of TLR4 by LPS and type 1 fimbriae (105, 229). This cooperative stimulation directly correlates with the level of cluster of differentiation 14 (CD14) expression on bladder cells (228). CD14 is an accessory molecule required for optimal TLR4 signaling in response to LPS (170). Immunohistochemical (IHC) analysis of human bladder biopsies revealed that CD14 expression is localized to the submucosa (106), suggesting that uroepithelial cells exposed to the lumen have little to no CD14 expression and therefore may not respond efficiently to LPS alone. These results support a role for both independent and cooperative TLR4 stimulation by UPEC fimbriae. Lastly, the FimH tip adhesin of type 1 fimbriae was recently shown to directly interact with TLR4, an additional means for LPS-independent stimulation by UPEC fimbriae (12, 175).

Infection of knockout mice has revealed critical roles for myeloid differentiation primary response protein 88 (MyD88), TIR domain-containing adaptor inducing beta interferon (TRIF), and TRIF-related adaptor molecule (TRAM) in signaling for UPEC clearance (73). It is also apparent that different fimbrial types influence the corresponding downstream signaling pathways (73). Regardless of the fimbria involved in stimulation, all pathways involving these adaptor molecules result in activation of NF-κB and proinflammatory gene expression. Song and colleagues identified an accompanying proinflammatory bladder cell signaling pathway that is also dependent on TLR4 but results in a spike in intracellular calcium levels (245). This calcium spike leads to adenylyl cyclase 3 (AC3)-mediated increase in cAMP, protein kinase A (PKA) activation, phosphorylation of the cAMP response element-binding protein transcription factor (CREB), and proinflammatory gene expression (245). In response to UPEC inoculation, cytokine secretion by the CREB pathway occurs faster (1 h) than NF-κB translocation to the nucleus (2 h) and can also be activated by TLR2 and TLR3 ligands (245).

Other TLR pathways have been implicated in host defense during UTI. tlr2−/− mice appear to respond normally to acute UTI (210). Conversely, tlr11−/− mice are more susceptible than wild-type mice to UPEC kidney infection (296). The TLR11 ligand is a profilin-like molecule that was isolated from Toxoplasma gondii (292). While structurally related proteins are present in other apicomplexan protozoa (292), a UPEC-encoded homolog has yet to be identified. The fact that there is a stop codon in the open reading frame of human genomic and cell line tlr11 sequences may help explain acute and recurrent UTI susceptibility in humans (296). In contrast to the kidney-specific role for TLR11 during UTI (296), TLR5 appears to play a UPEC recognition role in the bladder (7). TLR5 recognizes the structural subunit of flagella (101), which are essential for UPEC motility in the urinary tract (150, 152, 285). Flagellar expression peaks at 4 to 6 h postinoculation, coinciding with UPEC ascension of the ureters (150). At this time point, there is TLR5-dependent induction of inflammatory cytokines and chemokines (7). By day 5 postinoculation, tlr5−/− mice have increased inflammation and bacterial burdens compared to wild-type controls (7), highlighting the importance of early UPEC recognition to contain the infection.

Surface molecules other than TLRs are also involved in host-UPEC interactions. Upon UPEC exposure, the cytoplasmic tail of uroplakin IIIa undergoes phosphorylation, and intracellular calcium levels increase, presumably important events for uroepithelial cell apoptosis and exfoliation (259). Although uroplakin Ia is thought to be the main receptor for UPEC FimH in vivo (167, 256, 286), type 1 fimbriae may bind to a number of host molecules, including uroplakin complexes (259), extracellular matrix proteins (147, 207, 241), CD molecules (18, 85, 139), and integrins (65). The CD44 ligand, hyaluronic acid (HA), accumulates in the urinary tract during UTI; UPEC can bind HA, thereby facilitating interaction with CD44 and tissue invasion (218). In accordance with this, cd44−/− mice are more resistant to UPEC kidney colonization and successive dissemination (218). Also, there are still unidentified players in inflammation and clearance of UPEC. For example, LPS-responder C3H/OuJ mice were found to be equally susceptible to UTI as non-LPS-responder C3H/HeJ mice yet demonstrated elevated levels of inflammation (111), revealing a susceptibility locus to map.

UPEC has evolved mechanisms to counter host recognition and signaling. Clinical UPEC isolates encode the gene for TcpC, which has structural homology to the TIR domain of human TLR1 and binds to MyD88, thereby inhibiting cytokine responses (47). TcpC-mediated interference of MyD88 signaling is an immune evasion strategy particular to acute pathogens; targeting this major signaling “hub” deteriorates innate immune responses (38). In addition, Billips and colleagues noted that a type 1-fimbriated K12 strain elicited more robust cytokine secretion from cultured urothelial cells than UPEC strains (25). By screening UPEC transposon mutants, they identified a peptidoglycan permease (ampG) and an O-antigen ligase gene (waaL) responsible for the dulled cytokine secretion in response to uropathogenic strains (26). A similar screen also identified the rfa-rfb operons and surA, encoding genes important for LPS biosynthesis and OMP biogenesis, respectively (119). These results suggest that UPEC utilizes gene products that modify bacterial membrane (especially LPS) to evade immune recognition and highlight the potential importance of TLR stimulation involving fimbriae and other organelles.

HAND-TO-HAND COMBAT: BATTLE FOR PRECIOUS RESOURCES

That E. coli strains causing UTI have several functionally redundant systems dedicated to iron uptake (39, 44, 283) suggests that the urinary tract, like other host niches, is an iron-limited environment (19). Siderophores are secreted iron-chelating molecules that allow bacteria to scavenge free and host protein-bound iron (37, 184). Enterobactin, for instance, can bind free ferric ions with a higher affinity than transferrin (70), a host iron transport protein responsible for regulating the free iron concentration in serum (213, 279). A transferrin family member, lactoferrin, evokes antimicrobial activity by sequestering iron over a range of pH (279). Lactoferrin is secreted by kidney cells (2) and is found in neutrophil granules (49) and thus could be involved in combating UTI. Both transferrin and lactoferrin have been shown to evoke direct antimicrobial activity by disrupting Gram-negative membranes (61, 90).

In addition to iron sequestration, there are host factors that directly counter the action of siderophores. Early studies indicated that serum albumin, alone or in concert with other serum proteins, can impede bacterial siderophore function (143). In addition, the mammalian protein lipocalin 2 (Lcn2) can bind and sequester enterobactin and similar catecholate siderophores (70, 74, 88, 110). Lcn2 inhibits enterobactin-dependent propagation of E. coli in vitro, and lcn2−/− mice are unable to control systemic E. coli burdens as well as wild-type mice (74). Production of Lcn2 is induced by TLR4, implicating iron regulation as a part of the immune response to infection (74). Murine GeneChip and quantitative PCR (qPCR) analyses confirmed that Lcn2 mRNA is upregulated by the uroepithelium of infected mice (215). Interestingly, these results were obtained in C3H/HeJ mice, indicating that a TLR4-independent signaling pathway can activate transcription of the lcn2 gene in response to UTI. Not surprisingly, UPEC has evolved a mechanism to counter Lcn2 siderophore sequestration. Encoded within the iroA gene cluster are glycosyltransferases that modify enterobactin in such a way that it cannot be bound by Lcn2 (30, 71, 239). Thus, both the host and UPEC have systems in place to manage their own iron stores and to inhibit iron acquisition by the other—a molecular arms race for an essential nutrient.

The role for bacterial central metabolism during infection has only been recently appreciated (6, 69, 129). Genes important for glucose import were upregulated by the uroepithelium of C3H/HeJ mice experiencing UTI, possibly for either nutrient sequestration or energy to combat infection (215). This fact, coupled with the knowledge that UPEC does not chemotax toward glucose in vitro (151) or utilize glucose as a primary carbon source in vivo (6), implies that UPEC may have evolved to use alternative carbon sources in the urinary tract. These results imply that nutrient acquisition is also a crucial aspect of bacterial pathogenesis and the host response that may influence the outcome of UTI.

FRIENDLY FORCES: HOST FACTORS INVOLVED WITH INTRACELLULAR UPEC

Over the past 12 years there has been a growing body of literature revealing that UPEC appears to have three distinct intracellular lifestyle components within the urinary tract (66). The first is uptake by apical endocytosis of Rab27b+/CD63+ fusiform vesicles, which are subsequently recycled back to the cell surface and exocytosed (29). The other two pathways both begin with uptake into a membrane-bound compartment which can lead to either a quiescent nonreplicative existence (67, 179) or escape from compartmental life to undergo a highly replicative phase in the cell cytoplasm (131, 177). While internalization via the fusiform vesicle pathway may be a side effect of normal bladder epithelium function, cellular uptake by the other two pathways is perhaps intended by UPEC to establish a reservoir to persist in the urinary tract (67, 131, 138, 177, 179, 226). Indeed, UPEC has been shown to exist in the urinary tract for weeks, even after antibiotic treatment (138). Infection of 10 genetically distinct mouse strains also revealed that some strains were more susceptible to persistence than others, indicating that host hereditary components may also contribute to the ability of UPEC to persevere in the urinary tract (113).

Infected mouse bladder explants monitored by time lapse fluorescence videomicroscopy generated a model for the intracellular UPEC life cycle instigated after uptake in a membrane-bound compartment (nonfusiform vesicle route) (131). While the mechanism of compartmental escape remains undefined, once contained in cytoplasmic “intracellular bacterial communities” (IBCs), UPEC can undergo several changes in morphology, categorized as early, middle, and late IBC stages (8, 131). Late IBCs that escape exfoliation with umbrella cells contain filamentous UPEC that are not present in C3H/HeJ mice, indicating that this morphological change may be a bacterial stress response to TLR4-mediated immune activation (131, 177). This murine background also experienced increased incidence and severity of IBCs compared to immunocompetent mice (8, 84, 131). Urothelial cells proximal to IBCs in C3H/HeJ mice upregulate transferrin receptor, Lcn2, complement system components (C3, factor B, and CD55), and lysozyme (215). Involucrin and suprabasin transcripts were also increased, indicating that, in addition to gene products that function to eradicate bacteria, proteins important for epithelial integrity may be an imperative host response during UTI (215).

In vitro treatment of either 5637 cells with a small amount of the detergent saponin (67) or immortalized pediatric bladder cells with the cholesterol-sequestering drug filipin (24) recapitulates some in vivo features of intracellular UPEC. Additionally, much work has been done using the 5637 bladder epithelial cell line to further delineate molecular components and mechanisms surrounding UPEC intracellularity (29, 56, 64, 65, 67, 161, 162, 177, 229). UPEC internalization does not require bacterial viability (229) but is dependent on FimH (162). β1 and α3 integrins were shown to be receptors for Fim-mediated UPEC internalization, mediated by signaling through focal adhesion kinase (FAK) and, in contrast to an earlier study, Src family kinases (65, 162). FimH-dependent uptake requires microtubules, histone deacetylase 6, the kinesin-1 light chain, and aurora A kinase (53). In addition to the involvement of cytoskeletal proteins, tyrosine kinases, and phosphoinositide 3-kinase (PI3-K) (162), UPEC engulfment has also been reported to be cholesterol and dynamin dependent and modulated by calcium levels, clathrin, and clathrin adaptors (64). Additional work on dynamin revealed that the nitric oxide synthase (NOS) enzyme is responsible for chemically modifying dynamin, redistributing it to the membrane for bacterial internalization (281). As hinted by the cholesterol dependence, UPEC internalization is often reported to be associated with lipid rafts (18, 133), dependent on caveolin-1 and Rho-family GTP binding proteins (56, 161). The association with lipid rafts was confirmed in vivo; UPEC inoculation in the presence of a lipid raft-disrupting chemical decreased the number of intracellular bacteria in the murine bladder (56).

Notably, TLR4 also plays a noninflammatory role in host defense against UPEC by modulating the activity of the observed secretory and vesicular internalization pathways. TLR4-mediated PKA activation suppresses the lipid raft endocytic pathway (243), a possible effort to prevent the establishment of persistence reservoirs. Also along these lines, UPEC exocytosis in fusiform vesicles was actually accelerated by TLR4-mediated recognition of LPS and dependent on the activities of cAMP, Rab27b, caveolin-1, and the scaffolding protein MyRIP (244).

CHEMICAL WARFARE: ANTIMICROBIAL PEPTIDES, CYTOKINES, AND CHEMOKINES

Antimicrobial peptides (AMPs) are short positively charged peptides secreted by both epithelial and hematopoietic cells that disrupt bacterial membranes and can be chemotactic for certain immune cells (246, 293, 294). Human β-defensin-1 mRNA and protein were found in kidney tissue, implicating this AMP in host defense against UPEC (277). More convincingly, mice deficient in defb1, a murine homolog of human β-defensin, have a significantly higher incidence of bacteriuria (174). Murine β-defensin is also a dendritic cell (DC) ligand that instigates upregulation of costimulatory molecules and maturation (28). The human cathelicidin, LL-37, and its murine homolog, cathelin-related antimicrobial peptide (CRAMP), are secreted in response to UPEC exposure (46). Studies using CRAMP-deficient mice revealed that epithelial-derived CRAMP is important during the early stages of UTI while leukocyte-derived CRAMP likely functions later when bacteria penetrate the kidney epithelium (46).

Human C-X-C ligand 8 (hCXCL8; interleukin-8 [IL-8]) is the main chemoattractant for neutrophils in humans, and murine CXCL1 (mCXCL1) and mCXCL2 (also known as KC and MIP-2, respectively) are the functional mouse homologs of IL-8 (122). Bladder and kidney cell lines secrete IL-8 in response to UPEC (102, 229, 287). Human and murine studies both demonstrate that neutrophil migration to the UPEC-infected urinary tract is dependent on IL-8 (3, 4, 99, 169). Additionally, mCXCL2 secretion is dependent on TLR4, as secretion was deficient in infected C3H/HeJ mice (100). hCXCR1 and hCXCR2 are receptors for a number of chemokines, including IL-8 (122). Both are expressed in bladder and kidney biopsies, and transmigration studies indicated that hCXCR1 plays a dominant role in IL-8-dependent neutrophil migration (86). Consistent with this, children prone to pyelonephritis tend to have low hCXCR1 expression and heterozygous hCXCR1 polymorphisms (78, 210). hCXCR1 deficiency results in impaired bacterial clearance but, unlike TLR4 deficiency, with intact inflammatory signaling that ultimately results in tissue damage (210). Similarly, mice lacking mCXCR2 (the functional homolog for hCXCL1) experience subepithelial accumulation of neutrophils, increased bacterial titers, and renal scarring after UPEC inoculation (78, 86, 98). These data indicate that normal function of neutrophils, their chemotactic ligands, and their chemokine receptors are required for bacterial clearance without postinflammatory sequelae.

Despite ample information on IL-8 in vitro and in vivo, a complete picture of the cytokine and chemokine dynamics during UTI was lacking. In response, a longitudinal assessment using a Bio-Plex format was conducted (121). Chemokine (C-C motif) ligand 2 (CCL2 or MCP-1), CCL4 (or MIP-1b), CCL5 (or RANTES), CXCL1, IL-1β, IL-6, IL-12p40, IL-17, tumor necrosis factor alpha (TNF-α), and granulocyte-colony stimulating factor (G-CSF) were all upregulated in bladder homogenates from UPEC-infected C57BL/6 mice (121). These results agreed with patient and cell line data regarding upregulation of IL-6 in response to UPEC (103, 104). In mice, TNF-α expression was elevated at 1 h postinoculation for rapid mobilization of acute responses (121); this waned at later time points, likely to prevent the deleterious effects of uncontrolled TNF-α signaling (16). Expression of most cytokines and chemokines peaked around 24 h postinoculation, returning to near baseline at 2 weeks (121). These dynamics correlate well with the peak and resolution of bacterial burdens in C57BL/6 mice (121). One notable exception was IL-17, which was highly upregulated from 6 h to 1 week postinoculation, remaining above baseline through the 2-week experimental duration (121). Importantly, IL-17A (the Th17 signature cytokine) contributes to innate clearance of UPEC through a mechanism involving cytokine and chemokine secretion and macrophage and neutrophil influx (K. E. Sivick, M. A. Schaller, S. N. Smith, and H. L. T. Mobley, submitted for publication).

Similar to TLR adaptor molecule usage (73), the type of fimbriae expressed also seems to influence the repertoire of chemokines secreted. Specifically, kidney cells exposed to type 1-fimbriated UPEC secrete neutrophil-associated chemokines, while P fimbriae-stimulated cells secrete chemokines targeting antigen-presenting cell (APC)- and Th1-specific cytokines, exemplified by CCL2 and CCL5 expression (87). In addition, IFN-γ and IL-4 (signature cytokines of the Th1 and Th2 lineages, respectively) and IL-10 (a T-regulatory [Treg] effector cytokine) knockout mice were tested for susceptibility to both acute cystitis and pyelonephritis (130). While il4−/− and il10−/− mice appear to experience infection dynamics similar to the wild type, ifnγ−/− mice had increased incidence and severity of UTI (130), implying a role for IFN-γ and Th1-mediated inflammatory responses during UTI.

THE INFANTRY: NEUTROPHIL AND APC RESPONSES TO UPEC-MEDIATED UTI

Infected mouse bladders examined histologically display thickening of epithelium accompanied by robust infiltration of inflammatory cells and edema in the lamina propria (Fig. 1C and D) (124). Neutrophils are the most rapid and abundant responders to the infected urinary tract (4, 100, 124, 236). Efficient migration of neutrophils requires intracellular adhesion molecule 1 (ICAM-1) expression by epithelial cells and β2 integrin (CD11b/CD18) expression by neutrophils (3, 227). G-CSF is also required for the neutrophil response, and unexpectedly, mice with neutralized G-CSF are more resistant to UTI (121). Although monocyte/macrophage numbers were similar in anti-G-CSF-treated mice, cytokines important for macrophage activation were upregulated, potentially leading to accelerated clearance by enhanced phagocytic killing (121). Despite counterintuitive phenotypes with respect to cytokine knock-down, antibody-mediated knockdown of the neutrophil population confirmed their crucial role in bacterial clearance, especially within the kidney (100). Lastly, the electrostatic properties of the UPEC P fimbrial tip adhesin may interfere with neutrophil binding, a potential host response evasion tactic specific to the kidney (31, 254).

Compared to the neutrophil response, relatively little is known about APCs in the context of UTI. In mice, resident CD11c+ cells that express low to intermediate levels of F4/80 and CD11b macrophage markers were found in the kidney (144), while CD11c+ cells expressing the major histocompatibility class II activation marker were found in the bladder (109, 227). In spite of macrophage marker expression, CD11c+ kidney cells had physical and functional characteristics of DCs (144). At 24 h postinoculation, CD11c+ cells that migrate to the bladder did not express CD8α, Gr-1, or B220 and thus were not plasmacytoid or lymphoid but appeared to be TNF-α- and inducible NOS (iNOS)-producing (Tip)-DCs (62) that express intermediate levels of CD11b. Infection studies in mice lacking Tip-DCs suggested that they are not necessary for the host response to acute UTI (62). Since Tip-DCs are necessary for the generation of mucosal IgA (255), their role may lie in mediating the humoral response to UPEC. Similar to what was observed for DCs, there appears to be a resident population of macrophages in bladder tissue that increases by several orders of magnitude in response to UTI (63, 109, 121). Monocytes expressing high levels of Gr-1, which can give rise to macrophages or DCs, are also recruited to the bladder in response to UPEC infection. Release of these cells from the bone marrow was dependent on CCR2 (63), and, correspondingly, CCL2 is upregulated in the bladder response to UTI (121).

Some of the factors utilized by neutrophils, macrophages, and DCs for pathogen uptake and destruction have been described during UTI. iNOS generates the antimicrobial compound nitric oxide (NO) from l-arginine and was originally reported to be secreted by macrophages (108, 183, 248). Although iNOS is rapidly upregulated in the inoculated bladder (181), two independent groups reported that inos−/− mice are equally as susceptible to UTI as wild-type mice, suggesting that neuronal NOS, endothelial NOS, or myeloperoxidase may act as compensatory factors (132, 205). Alternatively or in addition, inos−/− animals may lack a colonization phenotype because there are several factors (Hfq and Nsr-regulated genes, polyamines, and flavohemoglobin) expressed by UPEC that enhance tolerance to reactive nitrogen species in vitro (34, 35, 148, 251), suggesting that NO production may be an ineffective host defense against UPEC. With respect to the complement system, it appears that UPEC is able to bind C3 to enter host uroepithelial cells via the surface receptors Crry or CD46 (157, 247). Correspondingly, c3−/− mice are more resistant to renal damage and infection (247). As C3 levels are significantly higher in the urine of UTI patients (157), UPEC may stimulate C3 production for pathogenic means or has evolved to exploit this host defense factor.

SPECIAL OPERATIONS: ILLs IN THE INNATE IMMUNE RESPONSE TO UPEC-MEDIATED UTI

Infection studies using severe combined immunodeficient (SCID) mice that lack functional B and T cells and nude mice that lack thymically derived T cells provide preliminary evidence of a role for innate-like lymphocytes (ILLs) in acute UTI host defense (115). Epithelial γδ T cells, B-1 cells, and natural killer T (NKT) cells are ILLs: cellular subsets that have relatively invariant receptors and reside in specific locations of the body (122). After a 2-day primary infection, SCID mice had significantly higher bacterial counts in their bladder and kidneys, while nude mice were colonized similarly to wild-type animals (115). The lack of a colonization phenotype in nude mice suggests that either antibody responses independent of thymus-derived T-cell help or extrathymically produced T cells may play a role in innate clearance of UPEC. The latter suggestion has some experimental support. γδ T cells can be produced extrathymically and rapidly secrete cytokines in response to stimulation (1, 17, 40, 45). Resident γδ T cells found in the bladder increase in response to UTI (163; also K. E. Sivick, M. A. Schaller, S. N. Smith, and H. L. T. Mobley, submitted for publication), and TCR δ−/− mice are more susceptible to UTI than isogenic controls (130). As γδ TCR+ cells express IL-17A during UPEC-mediated UTI (Sivick et al. submitted), this rapid-response cell population may function in concert with other innate factors to mediate neutrophil influx for clearance of UPEC. B-1 cells spontaneously secrete large quantities of polyspecific IgM against bacterial and self-antigens, and in contrast to conventional (B-2) B cells, do not require T-cell help (23). While IgM secreted by B-1 cells might play a role in innate clearance of UPEC, current evidence suggests otherwise. JHD mice, lacking both B-1 and B-2 cells (43, 212), infected and monitored over a 14-day time period exhibited no significant increase in incidence or severity of cystitis (130). On a final note regarding ILLs, administration of α-galactosylceramide (α-GalCer), a ligand for CD1d-restricted NKT cells, alleviates renal UPEC infection (168). Consistent with this, we have observed a resident population of NK1.1+ cells (potentially NK or NKT cells) in the bladder of C57BL/6 mice that increases in response to UTI (K. E. Sivick and H. L. T. Mobley, unpublished data). Studies using a systemic E. coli infection model suggested that, similar to γδ T cells, NKT cells may act as early amplifiers of the innate immune response to UTI by rapid cytokine secretion (182).

COVERT OPERATIONS: CELLULAR AND HUMORAL ADAPTIVE IMMUNE RESPONSES TO UPEC-MEDIATED UTI

Existing data regarding adaptive immune responses to UPEC are relatively limited. In a seminal study, Thumbikat and colleagues engineered a strain of UPEC to express ovalbumin to examine mechanisms behind antigen-specific adaptive immune responses in experimental UTI (260). In response to reinfection, CD4+ and CD8+ cells infiltrated the bladder and expressed the CD69 activation marker in the spleen (260), extending the findings of early IHC studies probing T- and B-cell populations in infected bladders (109). Furthermore, splenocytes, enriched splenic T cells, or serum antibodies from previously infected donor mice each protected wild-type naïve recipient mice against UPEC challenge (260). This result suggests that protection derived from natural infection is antibody mediated, as UPEC-specific antibody-secreting plasma cells could be present in both splenocyte and enriched T-cell preparations. As expected, transfers from naïve donor mice did not facilitate enhanced protection to recipients (260). This result is in contrast to a previous murine adoptive transfer study where SCID recipients receiving splenocytes from either naïve or vaccinated wild-type donors exhibited equal levels of enhanced clearance, despite the presence of antigen-specific plasma cells in the vaccinated donor cells (115). This result suggests that simply reconstituting immunosuppressed mice with lymphoid cells provides the means (likely stimulatory cytokines for phagocytic cells) for enhanced clearance. Conversely, wild-type recipient mice used in the former study only exhibited enhanced clearance when given cells or serum from antigen-educated, vaccinated donors (260), indicating that enhanced protection in individuals with intact immune systems will be provided only by stimulation of an effective adaptive immune response.

T-cell subsets are characterized by transcription factors and cytokines involved in their differentiation and the particular effector cytokines they secrete. To date, studies have not implicated a skew toward Th1- or Th2-mediated UTI immunity (5, 260). DC phagocytosis of infected apoptotic cells is the key event required for DCs to secrete the cytokine milieu necessary for Th17 development (262), and both DCs and infected apoptotic cells are present in the bladder during UTI. Despite this connection, IL-17A is dispensable for the generation of a protective response in a murine reinfection model, suggesting that Th17 cells may not play a role in adaptive responses to UPEC infection (Sivick et al., submitted). Similar to APCs and other lymphocytes, there are resident CD8+ cells in the bladder that increase in response to infection (260; also Sivick and Mobley, unpublished). We speculate that the observed CD8+ cells are either classical cytotoxic T cells or intraepithelial lymphocytes that exert cytotoxic effects on UPEC- or virus-infected cells or rapidly secrete cytokines to mobilize innate immune responses. Lastly, the role of Treg subsets in UTI host defense has not been formally examined.

Despite the lack of detail regarding T-cell responses to UTI, there is ample evidence for antibody-mediated clearance of UPEC. Since the 1970s, the genitourinary tract has been recognized as part of the secretory immune system (82, 261). UPEC-specific antibodies are detected in the urine of infected patients (202) and in the urine or serum of animals exposed to UPEC antigens (116, 217, 260, 264). Urinary IgG and IgA from UTI patients are capable of inhibiting UPEC adherence (58, 249, 263). Patient studies have also suggested that antibody responses to pyelonephritis are, in general, stronger and last longer than humoral responses to cystitis (80, 134, 135). Analysis of murine urine and serum samples collected before and after vaccination with OMP iron receptors allowed identification of immunological correlates of vaccine-induced protection against UTI (5). Specifically, levels of either urinary IgA or serum IgG (relative to serum IgM; denoted the class switch index) inversely correlated with bladder colonization in vaccinated mice (5). Presumably, urinary IgA plays a direct role in UPEC clearance from the bladder mucosa, while IgG may be a marker for class switching by B cells or also play a direct role in mucosal bacterial clearance. As mentioned earlier, infected JHD mice had wild-type levels of colonization in response to primary infection, suggesting that B cells have no role in innate clearance of UPEC (130). However, this result is not unexpected since both antigen presentation and antibody-mediated protection provided by B cells would likely play a role in adaptive responses, indicating a need for reevaluation of these mice in UPEC reinfection and vaccination challenge models.

RECONSTRUCTION AND RECOVERY: UROTHELIAL REGENERATION IN RESPONSE TO UPEC INFECTION

One of the consequences of UPEC infection is exfoliation of the superficial facet cell layer that lines the surface of the bladder lumen (10, 60, 81, 166, 176, 177, 189). Microarray analyses probing regenerative signals revealed that, in addition to genes involved in cell biological processes, inflammatory cytokines, chemokines, signaling molecules, and transcription factors are also upregulated in response to inoculation (180, 181). While regeneration itself appears to be a function of basal stem/progenitor cells in the transitional epithelium (180), studies of the gut epithelium unveiled macrophages as “cellular transceivers” that relay MyD88-dependent inputs from the epithelium to colonic epithelial progenitors via direct contact (209). Whether or not macrophages play a similar role in the urinary tract remains unknown.

THE WAY AHEAD: VACCINE AND IMMUNIZATION STRATEGIES

While treatments have been proposed to expel intracellular UPEC from the bladder (29, 179), an E. coli reservoir harboring potential UPEC strains will always be present in the intestine (127, 173, 291). The involvement of TLRs in the immune response to UTI and current knowledge of their ability to incite innate and direct adaptive responses make them attractive adjuvant candidates for UTI vaccines (149, 242). These and other mucosal adjuvants and variations in vaccination routes and schedules must be tested in an effort to generate UPEC-specific local and systemic antibodies (155, 204) and optimize production of immunological memory, not tolerance (42, 165). There is considerable work to be done to better understand the mechanisms of protective immunity against UPEC in the bladder. Specifically, available knockout mouse strains could be used to systematically evaluate the role of various receptors, signaling molecules, cytokines and chemokines, and cell types in controlling UPEC-mediated UTI and eliciting potent adaptive and memory immune responses. Ideally, the field can acquire insights on UTI immunity at a level suitable to rationally develop a much-needed vaccine that elicits sterilizing immunity against UPEC in the human urinary tract.

  • Copyright © 2010 American Society for Microbiology

REFERENCES

  1. 1.↵
    Abo, T. 1993. Extrathymic pathways of T-cell differentiation: a primitive and fundamental immune system. Microbiol. Immunol.37:247-258.
    OpenUrlCrossRefPubMedWeb of Science
  2. 2.↵
    Abrink, M., E. Larsson, A. Gobl, and L. Hellman. 2000. Expression of lactoferrin in the kidney: implications for innate immunity and iron metabolism. Kidney Int.57:2004-2010.
    OpenUrlCrossRefPubMed
  3. 3.↵
    Agace, W. W. 1996. The role of the epithelial cell in Escherichia coli induced neutrophil migration into the urinary tract. Eur. Respir. J.9:1713-1728.
    OpenUrlAbstract/FREE Full Text
  4. 4.↵
    Agace, W. W., S. R. Hedges, M. Ceska, and C. Svanborg. 1993. Interleukin-8 and the neutrophil response to mucosal Gram-negative infection. J. Clin. Invest.92:780-785.
    OpenUrlCrossRefPubMedWeb of Science
  5. 5.↵
    Alteri, C. J., E. C. Hagan, K. E. Sivick, S. N. Smith, and H. L. T. Mobley. 2009. Mucosal immunization with iron receptor antigens protects against urinary tract infection. PLoS Pathog.5:e1000586.
    OpenUrlCrossRefPubMed
  6. 6.↵
    Alteri, C. J., S. N. Smith, and H. L. T. Mobley. 2009. Fitness of Escherichia coli during urinary tract infection requires gluconeogenesis and the TCA cycle. PLoS Pathog.5:e1000448.
    OpenUrlCrossRefPubMedWeb of Science
  7. 7.↵
    Andersen-Nissen, E., T. R. Hawn, K. D. Smith, A. Nachman, A. E. Lampano, S. Uematsu, S. Akira, and A. Aderem. 2007. Cutting edge: TLR5−/− mice are more susceptible to Escherichia coli urinary tract infection. J. Immunol.178:4717-4720.
    OpenUrlAbstract/FREE Full Text
  8. 8.↵
    Anderson, G. G., J. J. Palermo, J. D. Schilling, R. Roth, J. Heuser, and S. J. Hultgren. 2003. Intracellular bacterial biofilm-like pods in urinary tract infections. Science301:105-107.
    OpenUrlAbstract/FREE Full Text
  9. 9.↵
    Apodaca, G. 2004. The uroepithelium: not just a passive barrier. Traffic5:117-128.
    OpenUrlCrossRefPubMedWeb of Science
  10. 10.↵
    Aronson, M., O. Medalia, D. Amichay, and O. Nativ. 1988. Endotoxin-induced shedding of viable uroepithelial cells is an antimicrobial defense mechanism. Infect. Immun.56:1615-1617.
    OpenUrlAbstract/FREE Full Text
  11. 11.↵
    Aronson, M., O. Medalia, L. Schori, D. Mirelman, N. Sharon, and I. Ofek. 1979. Prevention of colonization of the urinary tract of mice with Escherichia coli by blocking of bacterial adherence with methyl alpha-d-mannopyranoside. J. Infect. Dis.139:329-332.
    OpenUrlCrossRefPubMedWeb of Science
  12. 12.↵
    Ashkar, A. A., K. L. Mossman, B. K. Coombes, C. L. Gyles, and R. Mackenzie. 2008. FimH adhesin of type 1 fimbriae is a potent inducer of innate antimicrobial responses which requires TLR4 and type 1 interferon signaling. PLoS Pathog.4:e1000233.
    OpenUrlCrossRefPubMed
  13. 13.↵
    Avorn, J., M. Monane, J. H. Gurwitz, R. J. Glynn, I. Choodnovskiy, and L. A. Lipsitz. 1994. Reduction of bacteriuria and pyuria after ingestion of cranberry juice. JAMA271:751-754.
    OpenUrlCrossRefPubMedWeb of Science
  14. 14.↵
    Bäckhed, F., M. Söderhäll, P. Ekman, S. Normark, and A. Richter-Dahlfors. 2001. Induction of innate immune responses by Escherichia coli and purified lipopolysaccharide correlate with organ- and cell-specific expression of Toll-like receptors within the human urinary tract. Cell Microbiol.3:153-158.
    OpenUrlCrossRefPubMedWeb of Science
  15. 15.↵
    Baier, W., E. A. Sedelmeier, and W. G. Bessler. 1997. Studies on the immunogenicity of an Escherichia coli extract after oral application in mice. Arzneimittelforschung47:980-985.
    OpenUrlPubMed
  16. 16.↵
    Balkwill, F. 2009. Tumour necrosis factor and cancer. Nat. Rev. Cancer9:361-371.
    OpenUrlCrossRefPubMedWeb of Science
  17. 17.↵
    Bandeira, A., S. Itohara, M. Bonneville, O. Burlen-Defranoux, T. Mota-Santos, A. Coutinho, and S. Tonegawa. 1991. Extrathymic origin of intestinal intraepithelial lymphocytes bearing T-cell antigen receptor gamma delta. Proc. Nat. Acad. Sci. U. S. A.88:43-47.
    OpenUrlAbstract/FREE Full Text
  18. 18.↵
    Baorto, D. M., Z. Gao, R. Malaviya, M. L. Dustin, A. van der Merwe, D. M. Lublin, and S. N. Abraham. 1997. Survival of FimH-expressing enterobacteria in macrophages relies on glycolipid traffic. Nature389:636-639.
    OpenUrlCrossRefPubMedWeb of Science
  19. 19.↵
    Barasch, J., and K. Mori. 2004. Cell biology: iron thievery. Nature432:811-813.
    OpenUrlCrossRefPubMedWeb of Science
  20. 20.↵
    Barnes, P. J., and M. Karin. 1997. Nuclear factor-κB: a pivotal transcription factor in chronic inflammatory diseases. N. Engl. J. Med.336:1066-1071.
    OpenUrlCrossRefPubMedWeb of Science
  21. 21.↵
    Bates, J. M., H. M. Raffi, K. Prasadan, R. Mascarenhas, Z. Laszik, N. Maeda, S. J. Hultgren, and S. Kumar. 2004. Tamm-Horsfall protein knockout mice are more prone to urinary tract infection: rapid communication. Kidney Int.65:791-797.
    OpenUrlCrossRefPubMedWeb of Science
  22. 22.↵
    Bauer, H. W., S. Alloussi, G. Egger, H. M. Blumlein, G. Cozma, and C. C. Schulman. 2005. A long-term, multicenter, double-blind study of an Escherichia coli extract (OM-89) in female patients with recurrent urinary tract infections. Eur. Urol.47:542-548.
    OpenUrlCrossRefPubMed
  23. 23.↵
    Berland, R., and H. H. Wortis. 2002. Origins and functions of B-1 cells with notes on the role of CD5. Annu. Rev. Immun.20:253-300.
    OpenUrlCrossRefPubMedWeb of Science
  24. 24.↵
    Berry, R. E., D. J. Klumpp, and A. J. Schaeffer. 2009. Urothelial cultures support intracellular bacterial community formation by uropathogenic Escherichia coli. Infect. Immun.77:2762-2772.
    OpenUrlAbstract/FREE Full Text
  25. 25.↵
    Billips, B. K., S. G. Forrestal, M. T. Rycyk, J. R. Johnson, D. J. Klumpp, and A. J. Schaeffer. 2007. Modulation of host innate immune response in the bladder by uropathogenic Escherichia coli. Infect. Immun.75:5353-5360.
    OpenUrlAbstract/FREE Full Text
  26. 26.↵
    Billips, B. K., A. J. Schaeffer, and D. J. Klumpp. 2008. Molecular basis of uropathogenic Escherichia coli evasion of the innate immune response in the bladder. Infect. Immun.76:3891-3900.
    OpenUrlAbstract/FREE Full Text
  27. 27.↵
    Billips, B. K., R. E. Yaggie, J. P. Cashy, A. J. Schaeffer, and D. J. Klumpp. 2009. A live attenuated vaccine for the treatment of urinary tract infection by uropathogenic Escherichia coli. J. Infect. Dis.200:263-272.
    OpenUrlCrossRefPubMed
  28. 28.↵
    Biragyn, A., P. A. Ruffini, C. A. Leifer, E. Klyushnenkova, A. Shakhov, O. Chertov, A. K. Shirakawa, J. M. Farber, D. M. Segal, J. J. Oppenheim, and L. W. Kwak. 2002. Toll-like receptor 4-dependent activation of dendritic cells by β-defensin 2. Science298:1025-1029.
    OpenUrlAbstract/FREE Full Text
  29. 29.↵
    Bishop, B. L., M. J. Duncan, J. Song, G. Li, D. Zaas, and S. N. Abraham. 2007. Cyclic AMP-regulated exocytosis of Escherichia coli from infected bladder epithelial cells. Nat. Med.13:625-630.
    OpenUrlCrossRefPubMedWeb of Science
  30. 30.↵
    Bister, B., D. Bischoff, G. J. Nicholson, M. Valdebenito, K. Schneider, G. Winkelmann, K. Hantke, and R. D. Sussmuth. 2004. The structure of salmochelins: C-glucosylated enterobactins of Salmonella enterica. Biometals17:471-481.
    OpenUrlCrossRefPubMedWeb of Science
  31. 31.↵
    Blumenstock, E., and K. Jann. 1982. Adhesion of piliated Escherichia coli strains to phagocytes: differences between bacteria with mannose-sensitive pili and those with mannose-resistant pili. Infect. Immun.35:264-269.
    OpenUrlAbstract/FREE Full Text
  32. 32.↵
    Bolin, C. A., and A. E. Jensen. 1987. Passive immunization with antibodies against iron-regulated outer membrane proteins protects turkeys from Escherichia coli septicemia. Infect. Immun.55:1239-1242.
    OpenUrlAbstract/FREE Full Text
  33. 33.↵
    Bouckaert, J., J. Berglund, M. Schembri, E. De Genst, L. Cools, M. Wuhrer, C. S. Hung, J. Pinkner, R. Slattegard, A. Zavialov, D. Choudhury, S. Langermann, S. J. Hultgren, L. Wyns, P. Klemm, S. Oscarson, S. D. Knight, and H. De Greve. 2005. Receptor binding studies disclose a novel class of high-affinity inhibitors of the Escherichia coli FimH adhesin. Mol. Microbiol.55:441-455.
    OpenUrlCrossRefPubMed
  34. 34.↵
    Bower, J. M., H. B. Gordon-Raagas, and M. A. Mulvey. 2009. Conditioning of uropathogenic Escherichia coli for enhanced colonization of host. Infect. Immun.77:2104-2112.
    OpenUrlAbstract/FREE Full Text
  35. 35.↵
    Bower, J. M., and M. A. Mulvey. 2006. Polyamine-mediated resistance of uropathogenic Escherichia coli to nitrosative stress. J. Bacteriol.188:928-933.
    OpenUrlAbstract/FREE Full Text
  36. 36.↵
    Brandberg, A., D. Mellstrom, and G. Samsioe. 1987. Low dose oral estriol treatment in elderly women with urogenital infections. Acta Obstet. Gynecol. Scand. Suppl.140:33-38.
    OpenUrlPubMed
  37. 37.↵
    Braun, V., and M. Braun. 2002. Iron transport and signaling in Escherichia coli. FEBS Lett.529:78-85.
    OpenUrlCrossRefPubMedWeb of Science
  38. 38.↵
    Brodsky, I. E., and R. Medzhitov. 2009. Targeting of immune signalling networks by bacterial pathogens. Nat. Cell Biol.11:521-526.
    OpenUrlCrossRefPubMedWeb of Science
  39. 39.↵
    Brzuszkiewicz, E., H. Bruggemann, H. Liesegang, M. Emmerth, T. Olschlager, G. Nagy, K. Albermann, C. Wagner, C. Buchrieser, L. Emody, G. Gottschalk, J. Hacker, and U. Dobrindt. 2006. How to become a uropathogen: comparative genomic analysis of extraintestinal pathogenic Escherichia coli strains. Proc. Nat. Acad. Sci. U. S. A.103:12879-12884.
    OpenUrlAbstract/FREE Full Text
  40. 40.↵
    Carding, S. R., and P. J. Egan. 2002. γδ T cells: functional plasticity and heterogeneity. Nat. Rev. Immunol.2:336-345.
    OpenUrlCrossRefPubMedWeb of Science
  41. 41.↵
    Cardozo, L., C. Benness, and D. Abbott. 1998. Low dose oestrogen prophylaxis for recurrent urinary tract infections in elderly women. Br. J. Obstet. Gynaecol.105:403-407.
    OpenUrlCrossRefPubMedWeb of Science
  42. 42.↵
    Castellino, F., G. Galli, G. Del Giudice, and R. Rappuoli. 2009. Generating memory with vaccination. Eur. J. Immunol.39:2100-2105.
    OpenUrlCrossRefPubMedWeb of Science
  43. 43.↵
    Chen, J., M. Trounstine, F. W. Alt, F. Young, C. Kurahara, J. F. Loring, and D. Huszar. 1993. Immunoglobulin gene rearrangement in B cell deficient mice generated by targeted deletion of the JH locus. Int. Immunol.5:647-656.
    OpenUrlCrossRefPubMedWeb of Science
  44. 44.↵
    Chen, S. L., C. S. Hung, J. Xu, C. S. Reigstad, V. Magrini, A. Sabo, D. Blasiar, T. Bieri, R. R. Meyer, P. Ozersky, J. R. Armstrong, R. S. Fulton, J. P. Latreille, J. Spieth, T. M. Hooton, E. R. Mardis, S. J. Hultgren, and J. I. Gordon. 2006. Identification of genes subject to positive selection in uropathogenic strains of Escherichia coli: a comparative genomics approach. Proc. Nat. Acad. Sci. U. S. A.103:5977-5982.
    OpenUrlAbstract/FREE Full Text
  45. 45.↵
    Chien, Y.-H., R. Jores, and M. P. Crowley. 1996. Recognition by γδ T cells. Annu. Rev. Immunol.14:511-532.
    OpenUrlCrossRefPubMedWeb of Science
  46. 46.↵
    Chromek, M., Z. Slamova, P. Bergman, L. Kovacs, L. Podracka, I. Ehren, T. Hokfelt, G. H. Gudmundsson, R. L. Gallo, B. Agerberth, and A. Brauner. 2006. The antimicrobial peptide cathelicidin protects the urinary tract against invasive bacterial infection. Nat. Med.12:636-641.
    OpenUrlCrossRefPubMedWeb of Science
  47. 47.↵
    Cirl, C., A. Wieser, M. Yadav, S. Duerr, S. Schubert, H. Fischer, D. Stappert, N. Wantia, N. Rodriguez, H. Wagner, C. Svanborg, and T. Miethke. 2008. Subversion of toll-like receptor signaling by a unique family of bacterial Toll/interleukin-1 receptor domain-containing proteins. Nat. Med.14:399-406.
    OpenUrlCrossRefPubMedWeb of Science
  48. 48.↵
    Connell, I., W. Agace, P. Klemm, M. Schembri, S. Marild, and C. Svanborg. 1996. Type 1 fimbrial expression enhances Escherichia coli virulence for the urinary tract. Proc. Nat. Acad. Sci. U. S. A.93:9827-9832.
    OpenUrlAbstract/FREE Full Text
  49. 49.↵
    Cramer, E., K. Pryzwansky, J. Villeval, U. Testa, and J. Breton-Gorius. 1985. Ultrastructural localization of lactoferrin and myeloperoxidase in human neutrophils by immunogold. Blood65:423-432.
    OpenUrlAbstract/FREE Full Text
  50. 50.↵
    Czaja, C. A., D. Scholes, T. M. Hooton, and W. E. Stamm. 2007. Population-based epidemiologic analysis of acute pyelonephritis. Clin. Infect. Dis.45:273-280.
    OpenUrlCrossRefPubMedWeb of Science
  51. 51.↵
    Czerwionka-Szaflarska, M., and M. Pawlowska. 1996. Influence of Uro-Vaxom on sIgA level in urine in children with recurrent urinary tract infections. Arch. Immunol. Ther. Exp. (Warsz.)44:195-197.
    OpenUrlPubMed
  52. 52.↵
    Dethlefsen, L., S. Huse, M. L. Sogin, and D. A. Relman. 2008. The pervasive effects of an antibiotic on the human gut microbiota, as revealed by deep 16S rRNA sequencing. PLoS Biol.6:e280.
    OpenUrlCrossRefPubMed
  53. 53.↵
    Dhakal, B. K., and M. A. Mulvey. 2009. Uropathogenic Escherichia coli invades host cells via an HDAC6-modulated microtubule-dependent pathway. J. Biol. Chem.284:446-454.
    OpenUrlAbstract/FREE Full Text
  54. 54.↵
    Donnenberg, M. S., and R. A. Welch. 1996. Virulence determinants of uropathogenic Escherichia coli, p. 135-174. In H. L. T. Mobley and J. W. Warren (ed.), Urinary tract infections: molecular pathogenesis and clinical management. ASM Press, Washington, DC.
  55. 55.↵
    Dorhoi, A., and S. H. E. Kaufmann. 2009. Fine-tuning of T cell responses during infection. Curr. Opin. Immunol.21:367-377.
    OpenUrlCrossRefPubMed
  56. 56.↵
    Duncan, M. J., G. Li, J. S. Shin, J. L. Carson, and S. N. Abraham. 2004. Bacterial penetration of bladder epithelium through lipid rafts. J. Biol. Chem.279:18944-18951.
    OpenUrlAbstract/FREE Full Text
  57. 57.↵
    Durant, L., A. Metais, C. Soulama-Mouze, J. M. Genevard, X. Nassif, and S. Escaich. 2007. Identification of candidates for a subunit vaccine against extraintestinal pathogenic Escherichia coli. Infect. Immun.75:1916-1925.
    OpenUrlAbstract/FREE Full Text
  58. 58.↵
    Eden, C. S., L. A. Hanson, U. Jodal, U. Lindberg, and A. S. Akerlund. 1976. Variable adherence to normal human urinary-tract epithelial cells of Escherichia coli strains associated with various forms of urinary-tract infection. Lancet1:490-492.
    OpenUrlPubMedWeb of Science
  59. 59.↵
    Eisenstein, B. I. 1981. Phase variation of type 1 fimbriae in Escherichia coli is under transcriptional control. Science214:337-339.
    OpenUrlAbstract/FREE Full Text
  60. 60.↵
    Elliott, T. S., L. Reed, R. C. Slack, and M. C. Bishop. 1985. Bacteriology and ultrastructure of the bladder in patients with urinary tract infections. J. Infect.11:191-199.
    OpenUrlCrossRefPubMedWeb of Science
  61. 61.↵
    Ellison, R. T., III, T. J. Giehl, and F. M. LaForce. 1988. Damage of the outer membrane of enteric gram-negative bacteria by lactoferrin and transferrin. Infect. Immun.56:2774-2781.
    OpenUrlAbstract/FREE Full Text
  62. 62.↵
    Engel, D., U. Dobrindt, A. Tittel, P. Peters, J. Maurer, I. Gutgemann, B. Kaissling, W. Kuziel, S. Jung, and C. Kurts. 2006. Tumor necrosis factor alpha- and inducible nitric oxide synthase-producing dendritic cells are rapidly recruited to the bladder in urinary tract infection but are dispensable for bacterial clearance. Infect. Immun.74:6100-6107.
    OpenUrlAbstract/FREE Full Text
  63. 63.↵
    Engel, D. R., J. Maurer, A. P. Tittel, C. Weisheit, T. Cavlar, B. Schumak, A. Limmer, N. van Rooijen, C. Trautwein, F. Tacke, and C. Kurts. 2008. CCR2 mediates homeostatic and inflammatory release of Gr1high monocytes from the bone marrow, but is dispensable for bladder infiltration in bacterial urinary tract infection. J. Immunol.181:5579-5586.
    OpenUrlAbstract/FREE Full Text
  64. 64.↵
    Eto, D. S., H. B. Gordon, B. K. Dhakal, T. A. Jones, and M. A. Mulvey. 2008. Clathrin, AP-2, and the NPXY-binding subset of alternate endocytic adaptors facilitate FimH-mediated bacterial invasion of host cells. Cell Microbiol.10:2553-2567.
    OpenUrlCrossRefPubMedWeb of Science
  65. 65.↵
    Eto, D. S., T. A. Jones, J. L. Sundsbak, and M. A. Mulvey. 2007. Integrin-mediated host cell invasion by type 1-piliated uropathogenic Escherichia coli. PLoS Pathog.3:e100.
    OpenUrlCrossRefPubMed
  66. 66.↵
    Eto, D. S., and M. A. Mulvey. 2007. Flushing bacteria out of the bladder. Nat. Med.13:531-532.
    OpenUrlCrossRefPubMed
  67. 67.↵
    Eto, D. S., J. L. Sundsbak, and M. A. Mulvey. 2006. Actin-gated intracellular growth and resurgence of uropathogenic Escherichia coli. Cell Microbiol.8:704-717.
    OpenUrlCrossRefPubMedWeb of Science
  68. 68.↵
    Ewers, C., G. Li, H. Wilking, S. Kiessling, K. Alt, E. M. Antao, C. Laturnus, I. Diehl, S. Glodde, T. Homeier, U. Bohnke, H. Steinruck, H. C. Philipp, and L. H. Wieler. 2007. Avian pathogenic, uropathogenic, and newborn meningitis-causing Escherichia coli: how closely related are they? Int. J. Med. Microbiol.297:163-176.
    OpenUrlCrossRefPubMedWeb of Science
  69. 69.↵
    Fabich, A. J., S. A. Jones, F. Z. Chowdhury, A. Cernosek, A. Anderson, D. Smalley, J. W. McHargue, G. A. Hightower, J. T. Smith, S. M. Autieri, M. P. Leatham, J. J. Lins, R. L. Allen, D. C. Laux, P. S. Cohen, and T. Conway. 2008. Comparison of carbon nutrition for pathogenic and commensal Escherichia coli strains in the mouse intestine. Infect. Immun.76:1143-1152.
    OpenUrlAbstract/FREE Full Text
  70. 70.↵
    Fischbach, M. A., H. Lin, D. R. Liu, and C. T. Walsh. 2006. How pathogenic bacteria evade mammalian sabotage in the battle for iron. Nat. Chem. Biol.2:132-138.
    OpenUrlCrossRefPubMedWeb of Science
  71. 71.↵
    Fischbach, M. A., H. Lin, L. Zhou, Y. Yu, R. J. Abergel, D. R. Liu, K. N. Raymond, B. L. Wanner, R. K. Strong, C. T. Walsh, A. Aderem, and K. D. Smith. 2006. The pathogen-associated iroA gene cluster mediates bacterial evasion of lipocalin 2. Proc. Nat. Acad. Sci. U. S. A.103:16502-16507.
    OpenUrlAbstract/FREE Full Text
  72. 72.↵
    Fischer, H., P. Ellstrom, K. Ekstrom, L. Gustafsson, M. Gustafsson, and C. Svanborg. 2007. Ceramide as a TLR4 agonist; a putative signalling intermediate between sphingolipid receptors for microbial ligands and TLR4. Cell Microbiol.9:1239-1251.
    OpenUrlCrossRefPubMedWeb of Science
  73. 73.↵
    Fischer, H., M. Yamamoto, S. Akira, B. Beutler, and C. Svanborg. 2006. Mechanism of pathogen-specific TLR4 activation in the mucosa: fimbriae, recognition receptors and adaptor protein selection. Eur. J. Immunol.36:267-277.
    OpenUrlCrossRefPubMedWeb of Science
  74. 74.↵
    Flo, T. H., K. D. Smith, S. Sato, D. J. Rodriguez, M. A. Holmes, R. K. Strong, S. Akira, and A. Aderem. 2004. Lipocalin 2 mediates an innate immune response to bacterial infection by sequestrating iron. Nature432:917-921.
    OpenUrlCrossRefPubMedWeb of Science
  75. 75.↵
    Foxman, B. 1990. Recurring urinary tract infection: incidence and risk factors. Am. J. Public Health80:331-333.
    OpenUrlCrossRefPubMedWeb of Science
  76. 76.↵
    Foxman, B., M. Ki, and P. Brown. 2007. Antibiotic resistance and pyelonephritis. Clin. Infect. Dis.45:281-283.
    OpenUrlCrossRefPubMedWeb of Science
  77. 77.↵
    Franco, A. V. 2005. Recurrent urinary tract infections. Best Pract. Res. Clin. Obstet. Gynaecol.19:861-873.
    OpenUrlCrossRefPubMed
  78. 78.↵
    Frendeus, B., G. Godaly, L. Hang, D. Karpman, A. C. Lundstedt, and C. Svanborg. 2000. Interleukin 8 receptor deficiency confers susceptibility to acute experimental pyelonephritis and may have a human counterpart. J. Exp. Med.192:881-890.
    OpenUrlAbstract/FREE Full Text
  79. 79.↵
    Frendeus, B., C. Wachtler, M. Hedlund, H. Fischer, P. Samuelsson, M. Svensson, and C. Svanborg. 2001. Escherichia coli P fimbriae utilize the Toll-like receptor 4 pathway for cell activation. Mol. Microbiol.40:37-51.
    OpenUrlCrossRefPubMedWeb of Science
  80. 80.↵
    Fries, D., F. Delavelle, D. Mathieu, L. Jacques, and L. Renault. 1977. Antibodies in Escherichia coli urinary tract infection. Proc. Eur. Dial. Transplant Assoc.14:535-540.
    OpenUrlPubMed
  81. 81.↵
    Fukushi, Y., S. Orikasa, and M. Kagayama. 1979. An electron microscopic study of the interaction between vesical epitherlium and E. coli. Investig. Urol. (Berl.)17:61-68.
    OpenUrl
  82. 82.↵
    Ganguly, R., and R. H. Waldman. 1980. Local immunity and local immune responses. Prog. Allergy27:1-68.
    OpenUrlPubMed
  83. 83.↵
    Ganz, T. 2009. Iron in innate immunity: starve the invaders. Curr. Opin. Immunol.21:63-67.
    OpenUrlCrossRefPubMed
  84. 84.↵
    Garofalo, C. K., T. M. Hooton, S. M. Martin, W. E. Stamm, J. J. Palermo, J. I. Gordon, and S. J. Hultgren. 2007. Escherichia coli from urine of female patients with urinary tract infections is competent for intracellular bacterial community formation. Infect. Immun.75:52-60.
    OpenUrlAbstract/FREE Full Text
  85. 85.↵
    Gbarah, A., C. G. Gahmberg, I. Ofek, U. Jacobi, and N. Sharon. 1991. Identification of the leukocyte adhesion molecules CD11 and CD18 as receptors for type 1-fimbriated (mannose-specific) Escherichia coli. Infect. Immun.59:4524-4530.
    OpenUrlAbstract/FREE Full Text
  86. 86.↵
    Godaly, G., L. Hang, B. Frendeus, and C. Svanborg. 2000. Transepithelial neutrophil migration is CXCR1 dependent in vitro and is defective in IL-8 receptor knockout mice. J. Immunol.165:5287-5294.
    OpenUrlAbstract/FREE Full Text
  87. 87.↵
    Godaly, G., G. Otto, M. D. Burdick, R. M. Strieter, and C. Svanborg. 2007. Fimbrial lectins influence the chemokine repertoire in the urinary tract mucosa. Kidney Int.71:778-786.
    OpenUrlCrossRefPubMedWeb of Science
  88. 88.↵
    Goetz, D. H., M. A. Holmes, N. Borregaard, M. E. Bluhm, K. N. Raymond, and R. K. Strong. 2002. The neutrophil lipocalin NGAL is a bacteriostatic agent that interferes with siderophore-mediated iron acquisition. Mol. Cell10:1033-1043.
    OpenUrlCrossRefPubMedWeb of Science
  89. 89.
    Goluszko, P., E. Goluszko, B. Nowicki, S. Nowicki, V. Popov, and H. Q. Wang. 2005. Vaccination with purified Dr fimbriae reduces mortality associated with chronic urinary tract infection due to Escherichia coli bearing Dr adhesin. Infect. Immun.73:627-631.
    OpenUrlAbstract/FREE Full Text
  90. 90.↵
    González-Chávez, S. A., S. Arévalo-Gallegos, and Q. Rascón-Cruz. 2009. Lactoferrin: structure, function and applications. Int. J. Antimicrob. Agents33:301.e1-301.e8.
    OpenUrlCrossRefPubMed
  91. 91.↵
    Grischke, E. M., and H. Ruttgers. 1987. Treatment of bacterial infections of the female urinary tract by immunization of the patients. Urol. Int.42:338-341.
    OpenUrlCrossRefPubMed
  92. 92.↵
    Gunther, N. W., IV, J. A. Snyder, V. Lockatell, I. Blomfield, D. E. Johnson, and H. L. Mobley. 2002. Assessment of virulence of uropathogenic Escherichia coli type 1 fimbrial mutants in which the invertible element is phase-locked on or off. Infect. Immun.70:3344-3354.
    OpenUrlAbstract/FREE Full Text
  93. 93.↵
    Gupta, K., T. M. Hooton, C. L. Wobbe, and W. E. Stamm. 1999. The prevalence of antimicrobial resistance among uropathogens causing acute uncomplicated cystitis in young women. Int. J. Antimicrob. Agents11:305-308.
    OpenUrlCrossRefPubMedWeb of Science
  94. 94.↵
    Gupta, K., D. Scholes, and W. E. Stamm. 1999. Increasing prevalence of antimicrobial resistance among uropathogens causing acute uncomplicated cystitis in women. JAMA281:736-738.
    OpenUrlCrossRefPubMedWeb of Science
  95. 95.↵
    Hachen, H. J. 1990. Oral immunotherapy in paraplegic patients with chronic urinary tract infections: a double-blind, placebo-controlled trial. J. Urol.143:759-763.
    OpenUrlPubMed
  96. 96.↵
    Hagberg, L., R. Hull, S. Hull, J. R. McGhee, S. M. Michalek, and C. Svanborg Eden. 1984. Difference in susceptibility to gram-negative urinary tract infection between C3H/HeJ and C3H/HeN mice. Infect. Immun.46:839-844.
    OpenUrlAbstract/FREE Full Text
  97. 97.↵
    Hagberg, L., U. Jodal, T. K. Korhonen, G. Lidin-Janson, U. Lindberg, and C. Svanborg Eden. 1981. Adhesion, hemagglutination, and virulence of Escherichia coli causing urinary tract infections. Infect. Immun.31:564-570.
    OpenUrlAbstract/FREE Full Text
  98. 98.↵
    Hang, L., B. Frendeus, G. Godaly, and C. Svanborg. 2000. Interleukin-8 receptor knockout mice have subepithelial neutrophil entrapment and renal scarring following acute pyelonephritis. J. Infect. Dis.182:1738-1748.
    OpenUrlCrossRefPubMedWeb of Science
  99. 99.↵
    Hang, L., M. Haraoka, W. W. Agace, H. Leffler, M. Burdick, R. Strieter, and C. Svanborg. 1999. Macrophage inflammatory protein-2 is required for neutrophil passage across the epithelial barrier of the infected urinary tract. J. Immunol.162:3037-3044.
    OpenUrlAbstract/FREE Full Text
  100. 100.↵
    Haraoka, M., L. Hang, B. Frendeus, G. Godaly, M. Burdick, R. Strieter, and C. Svanborg. 1999. Neutrophil recruitment and resistance to urinary tract infection. J. Infect. Dis.180:1220-1229.
    OpenUrlCrossRefPubMedWeb of Science
  101. 101.↵
    Hayashi, F., K. D. Smith, A. Ozinsky, T. R. Hawn, E. C. Yi, D. R. Goodlett, J. K. Eng. S. Akira, D. M. Underhill, and A. Aderem. 2001. The innate immune response to bacterial flagellin is mediated by Toll-like receptor 5. Nature410:1099-1103.
    OpenUrlCrossRefPubMedWeb of Science
  102. 102.↵
    Hedges, S., W. Agace, M. Svensson, A. C. Sjogren, M. Ceska, and C. Svanborg. 1994. Uroepithelial cells are part of a mucosal cytokine network. Infect. Immun.62:2315-2321.
    OpenUrlAbstract/FREE Full Text
  103. 103.↵
    Hedges, S., P. Anderson, G. Lidin-Janson, P. de Man, and C. Svanborg. 1991. Interleukin-6 response to deliberate colonization of the human urinary tract with gram-negative bacteria. Infect. Immun.59:421-427.
    OpenUrlAbstract/FREE Full Text
  104. 104.↵
    Hedges, S., M. Svensson, and C. Svanborg. 1992. Interleukin-6 response of epithelial cell lines to bacterial stimulation in vitro. Infect. Immun.60:1295-1301.
    OpenUrlAbstract/FREE Full Text
  105. 105.↵
    Hedlund, M., B. Frendeus, C. Wachtler, L. Hang, H. Fischer, and C. Svanborg. 2001. Type 1 fimbriae deliver an LPS- and TLR4-dependent activation signal to CD14-negative cells. Mol. Microbiol.39:542-552.
    OpenUrlCrossRefPubMedWeb of Science
  106. 106.↵
    Hedlund, M., C. Wachtler, E. Johansson, L. Hang, J. E. Somerville, R. P. Darveau, and C. Svanborg. 1999. P fimbriae-dependent, lipopolysaccharide-independent activation of epithelial cytokine responses. Mol. Microbiol.33:693-703.
    OpenUrlCrossRefPubMedWeb of Science
  107. 107.↵
    Henderson, I. R., M. Meehan, and P. Owen. 1997. Antigen 43, a phase-variable bipartite outer membrane protein, determines colony morphology and autoaggregation in Escherichia coli K-12. FEMS Microbiol. Lett.149:115-120.
    OpenUrlCrossRefPubMedWeb of Science
  108. 108.↵
    Hibbs, J. B., Jr. 1991. Synthesis of nitric oxide from L-arginine: a recently discovered pathway induced by cytokines with antitumour and antimicrobial activity. Res. Immunol.142:565-569; discussion, 596-598.
    OpenUrlCrossRefPubMedWeb of Science
  109. 109.↵
    Hirose, T., Y. Kumamoto, M. Matsukawa, A. Yokoo, T. Satoh, and A. Matsuura. 1992. Study on local immune response in Escherichia coli-induced experimental urinary tract infection in mice—infiltration of Ia-positive cells, macrophages, neutrophils, T cells and B cells. Kansenshogaku Zasshi66:964-973.
    OpenUrlCrossRefPubMed
  110. 110.↵
    Holmes, M. A., W. Paulsene, X. Jide, C. Ratledge, and R. K. Strong. 2005. Siderocalin (Lcn 2) also binds carboxymycobactins, potentially defending against mycobacterial infections through iron sequestration. Structure13:29-41.
    OpenUrlCrossRefPubMed
  111. 111.↵
    Hopkins, W., A. Gendron-Fitzpatrick, D. O. McCarthy, J. E. Haine, and D. T. Uehling. 1996. Lipopolysaccharide-responder and nonresponder C3H mouse strains are equally susceptible to an induced Escherichia coli urinary tract infection. Infect. Immun.64:1369-1372.
    OpenUrlAbstract/FREE Full Text
  112. 112.↵
    Hopkins, W. J., J. Elkahwaji, L. M. Beierle, G. E. Leverson, and D. T. Uehling. 2007. Vaginal mucosal vaccine for recurrent urinary tract infections in women: results of a phase 2 clinical trial. J. Urol.177:1349-1353.
    OpenUrlCrossRefPubMedWeb of Science
  113. 113.↵
    Hopkins, W. J., A. Gendron-Fitzpatrick, E. Balish, and D. T. Uehling. 1998. Time course and host responses to Escherichia coli urinary tract infection in genetically distinct mouse strains. Infect. Immun.66:2798-2802.
    OpenUrlAbstract/FREE Full Text
  114. 114.↵
    Hopkins, W. J., D. M. Heisey, and D. T. Uehling. 1999. Association of human leucocyte antigen phenotype with vaccine efficacy in patients receiving vaginal mucosal immunization for recurrent urinary tract infection. Vaccine17:169-171.
    OpenUrlCrossRefPubMed
  115. 115.↵
    Hopkins, W. J., L. J. James, E. Balish, and D. T. Uehling. 1993. Congenital immunodeficiencies in mice increase susceptibility to urinary tract infection. J. Urol.149:922-925.
    OpenUrlPubMedWeb of Science
  116. 116.↵
    Hopkins, W. J., D. T. Uehling, and E. Balish. 1987. Local and systemic antibody responses accompany spontaneous resolution of experimental cystitis in cynomolgus monkeys. Infect. Immun.55:1951-1956.
    OpenUrlAbstract/FREE Full Text
  117. 117.↵
    Huber, M., W. Baier, A. Serr, and W. G. Bessler. 2000. Immunogenicity of an Escherichia coli extract after oral or intraperitoneal administration: induction of antibodies against pathogenic bacterial strains. Int. J. Immunopharmacol.22:57-68.
    OpenUrlCrossRefPubMed
  118. 118.↵
    Hull, R. A., W. H. Donovan, M. Del Terzo, C. Stewart, M. Rogers, and R. O. Darouiche. 2002. Role of type 1 fimbria- and P fimbria-specific adherence in colonization of the neurogenic human bladder by Escherichia coli. Infect. Immun.70:6481-6484.
    OpenUrlAbstract/FREE Full Text
  119. 119.↵
    Hunstad, D. A., S. S. Justice, C. S. Hung, S. R. Lauer, and S. J. Hultgren. 2005. Suppression of bladder epithelial cytokine responses by uropathogenic Escherichia coli. Infect. Immun.73:3999-4006.
    OpenUrlAbstract/FREE Full Text
  120. 120.↵
    Hurst, R. E. 1994. Structure, function, and pathology of proteoglycans and glycosaminoglycans in the urinary tract. World J. Urol.12:3-10.
    OpenUrlCrossRefPubMed
  121. 121.↵
    Ingersoll, M. A., K. A. Kline, H. V. Nielsen, and S. J. Hultgren. 2008. G-CSF induction early in uropathogenic Escherichia coli infection of the urinary tract modulates host immunity. Cell Microbiol.10:2568-2578.
    OpenUrlCrossRefPubMedWeb of Science
  122. 122.↵
    Janeway, C. 2005. Immunobiology: the immune system in health and disease, 6th ed. Garland Science, New York, NY.
  123. 123.↵
    Janeway, C. A., Jr. 1989. Approaching the asymptote? Evolution and revolution in immunology. Cold Spring Harbor Symp. Quant. Biol.54:1-13.
    OpenUrlAbstract/FREE Full Text
  124. 124.↵
    Johnson, D. E., C. V. Lockatell, R. G. Russell, J. R. Hebel, M. D. Island, A. Stapleton, W. E. Stamm, and J. W. Warren. 1998. Comparison of Escherichia coli strains recovered from human cystitis and pyelonephritis infections in transurethrally challenged mice. Infect. Immun.66:3059-3065.
    OpenUrlAbstract/FREE Full Text
  125. 125.↵
    Johnson, J. R. 1996. Treatment and prevention of urinary tract infections, p. 405-425. In H. L. T. Mobley and J. W. Warren (ed.), Urinary tract infections: molecular pathogenesis and clinical management. ASM Press, Washington, DC.
  126. 126.↵
    Johnson, J. R. 1991. Virulence factors in Escherichia coli urinary tract infection. Clin. Microbiol. Rev.4:80-128.
    OpenUrlAbstract/FREE Full Text
  127. 127.↵
    Johnson, J. R., J. J. Brown, U. B. Carlino, and T. A. Russo. 1998. Colonization with and acquisition of uropathogenic Escherichia coli as revealed by polymerase chain reaction-based detection. J. Infect. Dis.177:1120-1124.
    OpenUrlCrossRefPubMedWeb of Science
  128. 128.↵
    Johnson, J. R., and W. E. Stamm. 1989. Urinary tract infections in women: diagnosis and treatment. Ann. Intern. Med.111:906-917.
    OpenUrlCrossRefPubMedWeb of Science
  129. 129.↵
    Jones, S. A., M. Jorgensen, F. Z. Chowdhury, R. Rodgers, J. Hartline, M. P. Leatham, C. Struve, K. A. Krogfelt, P. S. Cohen, and T. Conway. 2008. Glycogen and maltose utilization by Escherichia coli O157:H7 in the mouse intestine. Infect. Immun.76:2531-2540.
    OpenUrlAbstract/FREE Full Text
  130. 130.↵
    Jones-Carson, J., E. Balish, and D. T. Uehling. 1999. Susceptibility of immunodeficient gene-knockout mice to urinary tract infection. J. Urol.161:338-341.
    OpenUrlCrossRefPubMedWeb of Science
  131. 131.↵
    Justice, S. S., C. Hung, J. A. Theriot, D. A. Fletcher, G. G. Anderson, M. J. Footer, and S. J. Hultgren. 2004. Differentiation and developmental pathways of uropathogenic Escherichia coli in urinary tract pathogenesis. Proc. Nat. Acad. Sci. U. S. A.101:1333-1338.
    OpenUrlAbstract/FREE Full Text
  132. 132.↵
    Kang, W. S., F. J. Tamarkin, M. A. Wheeler, and R. M. Weiss. 2004. Rapid up-regulation of endothelial nitric-oxide synthase in a mouse model of Escherichia coli lipopolysaccharide-induced bladder inflammation. J. Pharmacol. Exp. Ther.310:452-458.
    OpenUrlAbstract/FREE Full Text
  133. 133.↵
    Kansau, I., C. Berger, M. Hospital, R. Amsellem, V. Nicolas, A. L. Servin, and M.-F. Bernet-Camard. 2004. Zipper-like internalization of Dr-positive Escherichia coli by epithelial cells is preceded by an adhesin-induced mobilization of raft-associated molecules in the initial step of adhesion. Infect. Immun.72:3733-3742.
    OpenUrlAbstract/FREE Full Text
  134. 134.↵
    Kantele, A., T. Mottonen, K. Ala-Kaila, and H. S. Arvilommi. 2003. P fimbria-specific B cell responses in patients with urinary tract infection. J. Infect. Dis.188:1885-1891.
    OpenUrlCrossRefPubMed
  135. 135.↵
    Kantele, A., R. Papunen, E. Virtanen, T. Mottonen, L. Rasanen, K. Ala-Kaila, P. H. Makela, and H. Arvilommi. 1994. Antibody-secreting cells in acute urinary tract infection as indicators of local immune response. J. Infect. Dis.169:1023-1028.
    OpenUrlCrossRefPubMed
  136. 136.↵
    Kaper, J. B., J. P. Nataro, and H. L. Mobley. 2004. Pathogenic Escherichia coli. Nat. Rev. Microbiol.2:123-140.
    OpenUrlCrossRefPubMedWeb of Science
  137. 137.↵
    Kernéis, S., J.-M. Gabastou, M.-F. Bernet-Camard, M.-H. Coconnier, B. J. Nowicki, and A. L. Servin. 1994. Human cultured intestinal cells express attachment sites for uropathogenic Escherichia coli bearing adhesins of the Dr adhesin family. FEMS Microb. Lett.119:27-32.
    OpenUrlCrossRefPubMedWeb of Science
  138. 138.↵
    Kerrn, M. B., C. Struve, J. Blom, N. Frimodt-Moller, and K. A. Krogfelt. 2005. Intracellular persistence of Escherichia coli in urinary bladders from mecillinam-treated mice. J. Antimicrob. Chemother.55:383-386.
    OpenUrlCrossRefPubMedWeb of Science
  139. 139.↵
    Khan, N. A., Y. Kim, S. Shin, and K. S. Kim. 2007. FimH-mediated Escherichia coli K1 invasion of human brain microvascular endothelial cells. Cell Microbiol.9:169-178.
    OpenUrlCrossRefPubMed
  140. 140.↵
    Kjaergaard, B., S. Walter, A. Knudsen, B. Johansen, and H. Barlebo. 1990. Treatment with low-dose vaginal estradiol in post-menopausal women. A double-blind controlled trial. Ugeskr Laeger152:658-659. (In Danish.)
    OpenUrl
  141. 141.↵
    Klumpp, D. J., M. T. Rycyk, M. C. Chen, P. Thumbikat, S. Sengupta, and A. J. Schaeffer. 2006. Uropathogenic Escherichia coli induces extrinsic and intrinsic cascades to initiate urothelial apoptosis. Infect. Immun.74:5106-5113.
    OpenUrlAbstract/FREE Full Text
  142. 142.↵
    Klumpp, D. J., A. C. Weiser, S. Sengupta, S. G. Forrestal, R. A. Batler, and A. J. Schaeffer. 2001. Uropathogenic Escherichia coli potentiates type 1 pilus-induced apoptosis by suppressing NF-κB. Infect. Immun.69:6689-6695.
    OpenUrlAbstract/FREE Full Text
  143. 143.↵
    Konopka, K., and J. B. Neilands. 1984. Effect of serum albumin on siderophore-mediated utilization of transferrin iron. Biochemistry23:2122-2127.
    OpenUrlCrossRefPubMed
  144. 144.↵
    Kruger, T., D. Benke, F. Eitner, A. Lang, M. Wirtz, E. E. Hamilton-Williams, D. Engel, B. Giese, G. Muller-Newen, J. Floege, and C. Kurts. 2004. Identification and functional characterization of dendritic cells in the healthy murine kidney and in experimental glomerulonephritis. J. Am. Soc. Nephrol.15:613-621.
    OpenUrlAbstract/FREE Full Text
  145. 145.
    Kruze, D., K. Biro, K. Holzbecher, M. Andrial, and W. Bossart. 1992. Protection by a polyvalent vaccine against challenge infection and pyelonephritis. Urol. Res.20:177-181.
    OpenUrlCrossRefPubMed
  146. 146.↵
    Kruze, D., K. Holzbecher, M. Andrial, and W. Bossart. 1989. Urinary antibody response after immunisation with a vaccine against urinary tract infection. Urol. Res.17:361-366.
    OpenUrlCrossRefPubMed
  147. 147.↵
    Kukkonen, M., T. Raunio, R. Virkola, K. Lahteenmaki, P. H. Makela, P. Klemm, S. Clegg, and T. K. Korhonen. 1993. Basement membrane carbohydrate as a target for bacterial adhesion: binding of type I fimbriae of Salmonella enterica and Escherichia coli to laminin. Mol. Microbiol.7:229-237.
    OpenUrlCrossRefPubMed
  148. 148.↵
    Kulesus, R. R., K. Diaz-Perez, E. S. Slechta, D. S. Eto, and M. A. Mulvey. 2008. Impact of the RNA chaperone Hfq on the fitness and virulence potential of uropathogenic Escherichia coli. Infect. Immun.76:3019-3026.
    OpenUrlAbstract/FREE Full Text
  149. 149.↵
    Lahiri, A., P. Das, and D. Chakravortty. 2008. Engagement of TLR signaling as adjuvant: towards smarter vaccine and beyond. Vaccine26:6777-6783.
    OpenUrlCrossRefPubMedWeb of Science
  150. 150.↵
    Lane, M. C., C. J. Alteri, S. N. Smith, and H. L. Mobley. 2007. Expression of flagella is coincident with uropathogenic Escherichia coli ascension to the upper urinary tract. Proc. Natl. Acad. Sci. U. S. A.104:16669-16674.
    OpenUrlAbstract/FREE Full Text
  151. 151.↵
    Lane, M. C., A. L. Lloyd, T. A. Markyvech, E. C. Hagan, and H. L. Mobley. 2006. Uropathogenic Escherichia coli strains generally lack functional Trg and Tap chemoreceptors found in the majority of Escherichia coli strains strictly residing in the gut. J. Bacteriol.188:5618-5625.
    OpenUrlAbstract/FREE Full Text
  152. 152.↵
    Lane, M. C., V. Lockatell, G. Monterosso, D. Lamphier, J. Weinert, J. R. Hebel, D. E. Johnson, and H. L. Mobley. 2005. Role of motility in the colonization of uropathogenic Escherichia coli in the urinary tract. Infect. Immun.73:7644-7656.
    OpenUrlAbstract/FREE Full Text
  153. 153.↵
    Langermann, S., R. Mollby, J. E. Burlein, S. R. Palaszynski, C. G. Auguste, A. DeFusco, R. Strouse, M. A. Schenerman, S. J. Hultgren, J. S. Pinkner, J. Winberg, L. Guldevall, M. Soderhall, K. Ishikawa, S. Normark, and S. Koenig. 2000. Vaccination with FimH adhesin protects cynomolgus monkeys from colonization and infection by uropathogenic Escherichia coli. J. Infect. Dis.181:774-778.
    OpenUrlCrossRefPubMedWeb of Science
  154. 154.↵
    Langermann, S., S. Palaszynski, M. Barnhart, G. Auguste, J. S. Pinkner, J. Burlein, P. Barren, S. Koenig, S. Leath, C. H. Jones, and S. J. Hultgren. 1997. Prevention of mucosal Escherichia coli infection by FimH-adhesin-based systemic vaccination. Science276:607-611.
    OpenUrlAbstract/FREE Full Text
  155. 155.↵
    Layton, G. T., and A. M. Smithyman. 1983. The effects of oral and combined parenteral/oral immunization against an experimental Escherichia coli urinary tract infection in mice. Clin. Exp. Immunol.54:305-312.
    OpenUrlPubMed
  156. 156.↵
    Lettgen, B. 1996. Prevention of recurrent urinary tract infections in female children: OM-89 Immunotherapy compared with nitrofurantoin prophylaxis in a randomized pilot study. Curr. Ther. Res.57:464-475.
    OpenUrlCrossRef
  157. 157.↵
    Li, K., M. J. Feito, S. H. Sacks, and N. S. Sheerin. 2006. CD46 (membrane cofactor protein) acts as a human epithelial cell receptor for internalization of opsonized uropathogenic Escherichia coli. J. Immunol.177:2543-2551.
    OpenUrlAbstract/FREE Full Text
  158. 158.↵
    Lilly, J. D., and C. L. Parsons. 1990. Bladder surface glycosaminoglycans is a human epithelial permeability barrier. Surg. Gynecol. Obstet.171:493-496.
    OpenUrlPubMedWeb of Science
  159. 159.↵
    Litwin, M. S., C. S. Saigal, E. M. Yano, C. Avila, S. A. Geschwind, J. M. Hanley, G. F. Joyce, R. Madison, J. Pace, S. M. Polich, and M. Wang. 2005. Urologic diseases in America Project: analytical methods and principal findings. J. Urol.173:933-937.
    OpenUrlCrossRefPubMedWeb of Science
  160. 160.↵
    Magasi, P., J. Panovics, A. Illes, and M. Nagy. 1994. Uro-Vaxom and the management of recurrent urinary tract infection in adults: a randomized multicenter double-blind trial. Eur. Urol.26:137-140.
    OpenUrlPubMed
  161. 161.↵
    Martinez, J. J., and S. J. Hultgren. 2002. Requirement of Rho-family GTPases in the invasion of Type 1-piliated uropathogenic Escherichia coli. Cell Microbiol.4:19-28.
    OpenUrlCrossRefPubMedWeb of Science
  162. 162.↵
    Martinez, J. J., M. A. Mulvey, J. D. Schilling, J. S. Pinkner, and S. J. Hultgren. 2000. Type 1 pilus-mediated bacterial invasion of bladder epithelial cells. EMBO J.19:2803-2812.
    OpenUrlAbstract/FREE Full Text
  163. 163.↵
    Matsukawa, M., Y. Kumamoto, T. Hirose, and A. Matsuura. 1994. Tissue gamma/delta T cells in experimental urinary tract infection relationship between other immuno-competent cells. Kansenshogaku Zasshi68:1498-1511. (In Japanese.)
    OpenUrlCrossRefPubMed
  164. 164.↵
    Medzhitov, R., and C. A. Janeway. 1997. Innate immunity: the virtues of a nonclonal system of recognition. Cell91:295-298.
    OpenUrlCrossRefPubMedWeb of Science
  165. 165.↵
    Mestecky, J., M. W. Russell, and C. O. Elson. 2007. Perspectives on mucosal vaccines: is mucosal tolerance a barrier? J. Immunol.179:5633-5638.
    OpenUrlAbstract/FREE Full Text
  166. 166.↵
    Mills, M., K. C. Meysick, and A. D. O'Brien. 2000. Cytotoxic necrotizing factor type 1 of uropathogenic Escherichia coli kills cultured human uroepithelial 5637 cells by an apoptotic mechanism. Infect. Immun.68:5869-5880.
    OpenUrlAbstract/FREE Full Text
  167. 167.↵
    Min, G., M. Stolz, G. Zhou, F. Liang, P. Sebbel, D. Stoffler, R. Glockshuber, T.-T. Sun, U. Aebi, and X.-P. Kong. 2002. Localization of uroplakin Ia, the urothelial receptor for bacterial adhesin FimH, on the six inner domains of the 16 nm urothelial plaque particle. J. Mol. Biol.317:697-706.
    OpenUrlCrossRefPubMedWeb of Science
  168. 168.↵
    Minagawa, S., C. Ohyama, S. Hatakeyama, N. Tsuchiya, T. Kato, and T. Habuchi. 2005. Activation of natural killer T cells by alpha-galactosylceramide mediates clearance of bacteria in murine urinary tract infection. J. Urol.173:2171-2174.
    OpenUrlCrossRefPubMed
  169. 169.↵
    Mittal, R., S. Chhibber, S. Sharma, and K. Harjai. 2004. Macrophage inflammatory protein-2, neutrophil recruitment and bacterial persistence in an experimental mouse model of urinary tract infection. Microbes Infect.6:1326-1332.
    OpenUrlCrossRefPubMed
  170. 170.↵
    Miyake, K. 2006. Roles for accessory molecules in microbial recognition by Toll-like receptors. J. Endotoxin Res.12:195-204.
    OpenUrlCrossRefPubMedWeb of Science
  171. 171.↵
    Miyazaki, J., W. Ba-Thein, T. Kumao, H. Akaza, and H. Hayashi. 2002. Identification of a type III secretion system in uropathogenic Escherichia coli. FEMS Microbiol. Lett.212:221-228.
    OpenUrlCrossRefPubMedWeb of Science
  172. 172.↵
    Mobley, H. L., G. R. Chippendale, J. H. Tenney, R. A. Hull, and J. W. Warren. 1987. Expression of type 1 fimbriae may be required for persistence of Escherichia coli in the catheterized urinary tract. J. Clin. Microbiol.25:2253-2257.
    OpenUrlAbstract/FREE Full Text
  173. 173.↵
    Moreno, E., A. Andreu, C. Pigrau, M. A. Kuskowski, J. R. Johnson, and G. Prats. 2008. Relationship between Escherichia coli strains causing acute cystitis in women and the fecal E. coli population of the host. J. Clin. Microbiol.46:2529-2534.
    OpenUrlAbstract/FREE Full Text
  174. 174.↵
    Morrison, G., F. Kilanowski, D. Davidson, and J. Dorin. 2002. Characterization of the mouse beta defensin 1, Defb1, mutant mouse model. Infect. Immun.70:3053-3060.
    OpenUrlAbstract/FREE Full Text
  175. 175.↵
    Mossman, K. L., M. F. Mian, N. M. Lauzon, C. L. Gyles, B. Lichty, R. Mackenzie, N. Gill, and A. A. Ashkar. 2008. Cutting edge: FimH adhesin of type 1 fimbriae is a novel TLR4 ligand. J. Immunol.181:6702-6706.
    OpenUrlAbstract/FREE Full Text
  176. 176.↵
    Mulvey, M. A., Y. S. Lopez-Boado, C. L. Wilson, R. Roth, W. C. Parks, J. Heuser, and S. J. Hultgren. 1998. Induction and evasion of host defenses by type 1-piliated uropathogenic Escherichia coli. Science282:1494-1497.
    OpenUrlAbstract/FREE Full Text
  177. 177.↵
    Mulvey, M. A., J. D. Schilling, and S. J. Hultgren. 2001. Establishment of a persistent Escherichia coli reservoir during the acute phase of a bladder infection. Infect. Immun.69:4572-4579.
    OpenUrlAbstract/FREE Full Text
  178. 178.↵
    Murray, B. E., T. Alvarado, K. H. Kim, M. Vorachit, P. Jayanetra, M. M. Levine, I. Prenzel, M. Fling, L. Elwell, G. H. McCracken, et al. 1985. Increasing resistance to trimethoprim-sulfamethoxazole among isolates of Escherichia coli in developing countries. J. Infect. Dis.152:1107-1113.
    OpenUrlCrossRefPubMedWeb of Science
  179. 179.↵
    Mysorekar, I. U., and S. J. Hultgren. 2006. Mechanisms of uropathogenic Escherichia coli persistence and eradication from the urinary tract. Proc. Natl. Acad. Sci. U. S. A.103:14170-14175.
    OpenUrlAbstract/FREE Full Text
  180. 180.↵
    Mysorekar, I. U., M. Isaacson-Schmid, J. N. Walker, J. C. Mills, and S. J. Hultgren. 2009. Bone morphogenetic protein 4 signaling regulatesepithelial renewal in the urinary tract in response to uropathogenic infection. Cell Host Microbe5:463-475.
    OpenUrlCrossRefPubMedWeb of Science
  181. 181.↵
    Mysorekar, I. U., M. A. Mulvey, S. J. Hultgren, and J. I. Gordon. 2002. Molecular regulation of urothelial renewal and host defenses during infection with uropathogenic Escherichia coli. J. Biol. Chem.277:7412-7419.
    OpenUrlAbstract/FREE Full Text
  182. 182.↵
    Nagarajan, N. A., and M. Kronenberg. 2007. Invariant NKT cells amplify the innate immune response to lipopolysaccharide. J. Immunol.178:2706-2713.
    OpenUrlAbstract/FREE Full Text
  183. 183.↵
    Nathan, C. F., and J. B. Hibbs, Jr. 1991. Role of nitric oxide synthesis in macrophage antimicrobial activity. Curr. Opin. Immunol.3:65-70.
    OpenUrlCrossRefPubMedWeb of Science
  184. 184.↵
    Neilands, J. B. 1995. Siderophores: structure and function of microbial iron transport compounds. J. Biol. Chem.270:26723-26726.
    OpenUrlFREE Full Text
  185. 185.↵
    O'Hanley, P. 1996. Prospects for urinary tract infection vaccines, p. 405-425. In H. L. T. Mobley and J. W. Warren (ed.), Urinary tract infections: molecular pathogenesis and clinical management. ASM Press, Washington, DC.
  186. 186.↵
    O'Hanley, P., G. Lalonde, and G. Ji. 1991. Alpha-hemolysin contributes to the pathogenicity of piliated digalactoside-binding Escherichia coli in the kidney: efficacy of an alpha-hemolysin vaccine in preventing renal injury in the BALB/c mouse model of pyelonephritis. Infect. Immun.59:1153-1161.
    OpenUrlAbstract/FREE Full Text
  187. 187.↵
    O'Hanley, P., D. Lark, S. Falkow, and G. Schoolnik. 1985. Molecular basis of Escherichia coli colonization of the upper urinary tract in BALB/c mice. Gal-Gal pili immunization prevents Escherichia coli pyelonephritis in the BALB/c mouse model of human pyelonephritis. J. Clin. Invest.75:347-360.
    OpenUrlCrossRefPubMedWeb of Science
  188. 188.↵
    O'Hanley, P., D. Low, I. Romero, D. Lark, K. Vosti, S. Falkow, and G. Schoolnik. 1985. Gal-Gal binding and hemolysin phenotypes and genotypes associated with uropathogenic Escherichia coli. N. Engl. J. Med.313:414-420.
    OpenUrlCrossRefPubMedWeb of Science
  189. 189.↵
    Orikasa, S., and F. Hinman, Jr. 1977. Reaction of the vesical wall to bacterial penetration: resistance to attachment, desquamation, and leukocytic activity. Invest. Urol.15:185-193.
    OpenUrlPubMedWeb of Science
  190. 190.↵
    Orskov, I., A. Ferencz, and F. Orskov. 1980. Tamm-Horsfall protein or uromucoid is the normal urinary slime that traps type 1 fimbriated Escherichia coli. Lancet1:887.
    OpenUrlPubMedWeb of Science
  191. 191.↵
    Orskov, I., and F. Orskov. 1983. Serology of Escherichia coli fimbriae. Prog. Allergy33:80-105.
    OpenUrlPubMedWeb of Science
  192. 192.↵
    Orskov, I., F. Orskov, and A. Birch-Andersen. 1980. Comparison of Escherichia coli fimbrial antigen F7 with type 1 fimbriae. Infect. Immun.27:657-666.
    OpenUrlAbstract/FREE Full Text
  193. 193.↵
    Pak, J., Y. Pu, Z. T. Zhang, D. L. Hasty, and X. R. Wu. 2001. Tamm-Horsfall protein binds to type 1 fimbriated Escherichia coli and prevents E. coli from binding to uroplakin Ia and Ib receptors. J. Biol. Chem.276:9924-9930.
    OpenUrlAbstract/FREE Full Text
  194. 194.↵
    Palaszynski, S., J. Pinkner, S. Leath, P. Barren, C. G. Auguste, J. Burlein, S. Hultgren, and S. Langermann. 1998. Systemic immunization with conserved pilus-associated adhesins protects against mucosal infections. Dev. Biol. Stand.92:117-122.
    OpenUrlPubMed
  195. 195.↵
    Parkkinen, J., R. Virkola, and T. K. Korhonen. 1988. Identification of factors in human urine that inhibit the binding of Escherichia coli adhesins. Infect. Immun.56:2623-2630.
    OpenUrlAbstract/FREE Full Text
  196. 196.↵
    Parsons, C. L., D. Boychuk, S. Jones, R. Hurst, and H. Callahan. 1990. Bladder surface glycosaminoglycans: an epithelial permeability barrier. J. Urol.143:139-142.
    OpenUrlPubMedWeb of Science
  197. 197.↵
    Parsons, C. L., C. Greenspan, S. W. Moore, and S. G. Mulholland. 1977. Role of surface mucin in primary antibacterial defense of bladder. Urology9:48-52.
    OpenUrlCrossRefPubMed
  198. 198.↵
    Parsons, C. L., and J. D. Schmidt. 1982. Control of recurrent lower urinary tract infection in the postmenopausal woman. J. Urol.128:1224-1226.
    OpenUrlPubMed
  199. 199.↵
    Parsons, C. L., C. W. Stauffer, and J. D. Schmidt. 1988. Reversible inactivation of bladder surface glycosaminoglycan antibacterial activity by protamine sulfate. Infect. Immun.56:1341-1343.
    OpenUrlAbstract/FREE Full Text
  200. 200.↵
    Patel, N., and I. R. Daniels. 2000. Botanical perspectives on health: of cystitis and cranberries. J. R. Soc. Health120:52-53.
    OpenUrlCrossRef
  201. 201.↵
    Patole, P. S., S. Schubert, K. Hildinger, S. Khandoga, A. Khandoga, S. Segerer, A. Henger, M. Kretzler, M. Werner, F. Krombach, D. Schlondorff, and H.-J. Anders. 2005. Toll-like receptor-4: renal cells and bone marrow cells signal for neutrophil recruitment during pyelonephritis. Kidney Int.68:2582-2587.
    OpenUrlCrossRefPubMedWeb of Science
  202. 202.↵
    Pearsall, N. N., and J. C. Sherris. 1966. The demonstration of specific urinary anti-bodies in urinary tract infections caused by Gram-negative bacilli. J. Pathol. Bacteriol.91:589-595.
    OpenUrlCrossRefPubMedWeb of Science
  203. 203.↵
    Pizarro-Cerdá, J., and P. Cossart. 2006. Bacterial adhesion and entry into host cells. Cell124:715-727.
    OpenUrlCrossRefPubMedWeb of Science
  204. 204.↵
    Poggio, T. V., J. L. La Torre, and E. A. Scodeller. 2006. Intranasal immunization with a recombinant truncated FimH adhesin adjuvanted with CpG oligodeoxynucleotides protects mice against uropathogenic Escherichia coli challenge. Can. J. Microbiol.52:1093-1102.
    OpenUrlCrossRefPubMedWeb of Science
  205. 205.↵
    Poljakovic, M., and K. Persson. 2003. Urinary tract infection in iNOS-deficient mice with focus on bacterial sensitivity to nitric oxide. Am. J. Physiol. Renal Physiol.284:F22-31.
    OpenUrlCrossRefPubMedWeb of Science
  206. 206.↵
    Poltorak, A., X. He, I. Smirnova, M. Y. Liu, C. Van Huffel, X. Du, D. Birdwell, E. Alejos, M. Silva, C. Galanos, M. Freudenberg, P. Ricciardi-Castagnoli, B. Layton, and B. Beutler. 1998. Defective LPS signaling in C3H/HeJ and C57BL/10ScCr mice: mutations in Tlr4 gene. Science282:2085-2088.
    OpenUrlAbstract/FREE Full Text
  207. 207.↵
    Pouttu, R., T. Puustinen, R. Virkola, J. Hacker, P. Klemm, and T. K. Korhonen. 1999. Amino acid residue Ala-62 in the FimH fimbrial adhesin is critical for the adhesiveness of meningitis-associated Escherichia coli to collagens. Mol. Microbiol.31:1747-1757.
    OpenUrlCrossRefPubMedWeb of Science
  208. 208.↵
    Privette, M., R. Cade, J. Peterson, and D. Mars. 1988. Prevention of recurrent urinary tract infections in postmenopausal women. Nephron50:24-27.
    OpenUrlCrossRefPubMedWeb of Science
  209. 209.↵
    Pull, S. L., J. M. Doherty, J. C. Mills, J. I. Gordon, and T. S. Stappenbeck. 2005. Activated macrophages are an adaptive element of the colonic epithelial progenitor niche necessary for regenerative responses to injury. Proc. Nat. Acad. Sci. U. S. A.102:99-104.
    OpenUrlAbstract/FREE Full Text
  210. 210.↵
    Ragnarsdóttir, B., H. Fischer, G. Godaly, J. Grönberg-Hernandez, M. Gustafsson, D. Karpman, A. C. Lundstedt, N. Lutay, S. Rämisch, M. L. Svensson, B. Wullt, M. Yadav, and C. Svanborg. 2008. TLR- and CXCR1-dependent innate immunity: insights into the genetics of urinary tract infections. Eur. J. Clin. Invest.38:12-20.
    OpenUrlCrossRefPubMed
  211. 211.↵
    Ragnarsdottir, B., M. Samuelsson, M. C. Gustafsson, I. Leijonhufvud, D. Karpman, and C. Svanborg. 2007. Reduced Toll-like receptor 4 expression in children with asymptomatic bacteriuria. J. Infect. Dis.196:475-484.
    OpenUrlCrossRefPubMedWeb of Science
  212. 212.↵
    Ramalingam, T., B. Rajan, J. Lee, and T. V. Rajan. 2003. Kinetics of cellular responses to intraperitoneal Brugia pahangi infections in normal and immunodeficient mice. Infect. Immun.71:4361-4367.
    OpenUrlCrossRefPubMed
  213. 213.↵
    Raymond, K. N., E. A. Dertz, and S. S. Kim. 2003. Enterobactin: An archetype for microbial iron transport. Proc. Nat. Acad. Sci. U. S. A.100:3584-3588.
    OpenUrlAbstract/FREE Full Text
  214. 214.↵
    Raz, R., and W. E. Stamm. 1993. A controlled trial of intravaginal estriol in postmenopausal women with recurrent urinary tract infections. N. Engl. J. Med.329:753-756.
    OpenUrlCrossRefPubMedWeb of Science
  215. 215.↵
    Reigstad, C. S., S. J. Hultgren, and J. I. Gordon. 2007. Functional genomic studies of uropathogenic Escherichia coli and host urothelial cells when intracellular bacterial communities are assembled. J. Biol. Chem.282:21259-21267.
    OpenUrlAbstract/FREE Full Text
  216. 216.↵
    Roberts, J. A., K. Hardaway, B. Kaack, E. N. Fussell, and G. Baskin. 1984. Prevention of pyelonephritis by immunization with P-fimbriae. J. Urol.131:602-607.
    OpenUrlCrossRefPubMedWeb of Science
  217. 217.↵
    Roberts, J. A., M. B. Kaack, G. Baskin, M. R. Chapman, D. A. Hunstad, J. S. Pinkner, and S. J. Hultgren. 2004. Antibody responses and protection from pyelonephritis following vaccination with purified Escherichia coli PapDG protein. J. Urol.171:1682-1685.
    OpenUrlCrossRefPubMedWeb of Science
  218. 218.↵
    Rouschop, K. M., M. Sylva, G. J. Teske, I. Hoedemaeker, S. T. Pals, J. J. Weening, T. van der Poll, and S. Florquin. 2006. Urothelial CD44 facilitates Escherichia coli infection of the murine urinary tract. J. Immunol.177:7225-7232.
    OpenUrlAbstract/FREE Full Text
  219. 219.↵
    Russo, T. A., J. M. Beanan, R. Olson, S. A. Genagon, U. MacDonald, J. J. Cope, B. A. Davidson, B. Johnston, and J. R. Johnson. 2007. A killed, genetically engineered derivative of a wild-type extraintestinal pathogenic Escherichia coli strain is a vaccine candidate. Vaccine25:3859-3870.
    OpenUrlCrossRefPubMedWeb of Science
  220. 220.↵
    Russo, T. A., and J. R. Johnson. 2003. Medical and economic impact of extraintestinal infections due to Escherichia coli: focus on an increasingly important endemic problem. Microbes Infect.5:449-456.
    OpenUrlCrossRefPubMedWeb of Science
  221. 221.↵
    Russo, T. A., and J. R. Johnson. 2000. Proposal for a new inclusive designation for extraintestinal pathogenic isolates of Escherichia coli: ExPEC. J. Infect. Dis.181:1753-1754.
    OpenUrlCrossRefPubMedWeb of Science
  222. 222.↵
    Russo, T. A., C. D. McFadden, U. B. Carlino-MacDonald, J. M. Beanan, T. J. Barnard, and J. R. Johnson. 2002. IroN functions as a siderophore receptor and is a urovirulence factor in an extraintestinal pathogenic isolate of Escherichia coli. Infect. Immun.70:7156-7160.
    OpenUrlAbstract/FREE Full Text
  223. 223.↵
    Russo, T. A., C. D. McFadden, U. B. Carlino-MacDonald, J. M. Beanan, R. Olson, and G. E. Wilding. 2003. The siderophore receptor IroN of extraintestinal pathogenic Escherichia coli is a potential vaccine candidate. Infect. Immun.71:7164-7169.
    OpenUrlAbstract/FREE Full Text
  224. 224.↵
    Ruttgers, H., and E. Grischke. 1987. Elevation of secretory IgA antibodies in the urinary tract by immunostimulation for the pre-operative treatment and post-operative prevention of urinary tract infections. Urol. Int.42:424-426.
    OpenUrlPubMed
  225. 225.↵
    Saemann, M. D., T. Weichhart, M. Zeyda, G. Staffler, M. Schunn, K. M. Stuhlmeier, Y. Sobanov, T. M. Stulnig, S. Akira, A. von Gabain, U. von Ahsen, W. H. Horl, and G. J. Zlabinger. 2005. Tamm-Horsfall glycoprotein links innate immune cell activation with adaptive immunity via a Toll-like receptor-4-dependent mechanism. J. Clin. Invest.115:468-475.
    OpenUrlCrossRefPubMedWeb of Science
  226. 226.↵
    Schilling, J. D., R. G. Lorenz, and S. J. Hultgren. 2002. Effect of trimethoprim-sulfamethoxazole on recurrent bacteriuria and bacterial persistence in mice infected with uropathogenic Escherichia coli. Infect. Immun.70:7042-7049.
    OpenUrlAbstract/FREE Full Text
  227. 227.↵
    Schilling, J. D., S. M. Martin, C. S. Hung, R. G. Lorenz, and S. J. Hultgren. 2003. Toll-like receptor 4 on stromal and hematopoietic cells mediates innate resistance to uropathogenic Escherichia coli. Proc. Nat. Acad. Sci. U. S. A.100:4203-4208.
    OpenUrlAbstract/FREE Full Text
  228. 228.↵
    Schilling, J. D., S. M. Martin, D. A. Hunstad, K. P. Patel, M. A. Mulvey, S. S. Justice, R. G. Lorenz, and S. J. Hultgren. 2003. CD14- and Toll-like receptor-dependent activation of bladder epithelial cells by lipopolysaccharide and type 1 piliated Escherichia coli. Infect. Immun.71:1470-1480.
    OpenUrlAbstract/FREE Full Text
  229. 229.↵
    Schilling, J. D., M. A. Mulvey, C. D. Vincent, R. G. Lorenz, and S. J. Hultgren. 2001. Bacterial invasion augments epithelial cytokine responses to Escherichia coli through a lipopolysaccharide-dependent mechanism. J. Immunol.166:1148-1155.
    OpenUrlAbstract/FREE Full Text
  230. 230.↵
    Schmidhammer, S., R. Ramoner, L. Holtl, G. Bartsch, M. Thurnher, and C. Zelle-Rieser. 2002. An Escherichia coli-based oral vaccine against urinary tract infections potently activates human dendritic cells. Urology60:521-526.
    OpenUrlCrossRefPubMedWeb of Science
  231. 231.↵
    Schmidt, M. A., P. O'Hanley, D. Lark, and G. K. Schoolnik. 1988. Synthetic peptides corresponding to protective epitopes of Escherichia coli digalactoside-binding pilin prevent infection in a murine pyelonephritis model. Proc. Nat. Acad. Sci. U. S. A.85:1247-1251.
    OpenUrlAbstract/FREE Full Text
  232. 232.↵
    Schulman, C. C., A. Corbusier, H. Michiels, and H. J. Taenzer. 1993. Oral immunotherapy of recurrent urinary tract infections: a double-blind placebo-controlled multicenter study. J. Urol.150:917-921.
    OpenUrlPubMedWeb of Science
  233. 233.↵
    Sedelmeier, E. A., and W. G. Bessler. 1995. Biological activity of bacterial cell-wall components: immunogenicity of the bacterial extract OM-89. Immunopharmacology29:29-36.
    OpenUrlCrossRefPubMed
  234. 234.
    Selsted, M. E., and A. J. Ouellette. 2005. Mammalian defensins in the antimicrobial immune response. Nat. Immunol.6:551-557.
    OpenUrlCrossRefPubMedWeb of Science
  235. 235.↵
    Servin, A. L. 2005. Pathogenesis of Afa/Dr Diffusely Adhering Escherichia coli. Clin. Microbiol. Rev.18:264-292.
    OpenUrlAbstract/FREE Full Text
  236. 236.↵
    Shahin, R. D., I. Engberg, L. Hagberg, and C. Svanborg Eden. 1987. Neutrophil recruitment and bacterial clearance correlated with LPS responsiveness in local gram-negative infection. J. Immunol.138:3475-3480.
    OpenUrlAbstract
  237. 237.↵
    Shrom, S. H., C. L. Parsons, and S. G. Mulholland. 1977. Role of urothelial surface mucoprotein in intrinsic bladder defense. Urology9:526-533.
    OpenUrlCrossRefPubMed
  238. 238.↵
    Sivick, K. E., and H. L. T. Mobley. 2009. An “omics” approach to uropathogenic Escherichia coli vaccinology. Trends Microbiol.17:431-432.
    OpenUrlCrossRefPubMedWeb of Science
  239. 239.↵
    Smith, K. D. 2007. Iron metabolism at the host pathogen interface: lipocalin 2 and the pathogen-associated iroA gene cluster. Int. J. Biochem. Cell Biol.39:1776-1780.
    OpenUrlCrossRefPubMed
  240. 240.↵
    Snyder, J. A., A. L. Lloyd, C. V. Lockatell, D. E. Johnson, and H. L. Mobley. 2006. Role of phase variation of type 1 fimbriae in a uropathogenic Escherichia coli cystitis isolate during urinary tract infection. Infect. Immun.74:1387-1393.
    OpenUrlAbstract/FREE Full Text
  241. 241.↵
    Sokurenko, E. V., H. S. Courtney, S. N. Abraham, P. Klemm, and D. L. Hasty. 1992. Functional heterogeneity of type 1 fimbriae of Escherichia coli. Infect. Immun.60:4709-4719.
    OpenUrlAbstract/FREE Full Text
  242. 242.↵
    Song, J., and S. N. Abraham. 2008. TLR-mediated immune responses in the urinary tract. Curr. Opin. Microbiol.11:66-73.
    OpenUrlCrossRefPubMedWeb of Science
  243. 243.↵
    Song, J., B. L. Bishop, G. Li, M. J. Duncan, and S. N. Abraham. 2007. TLR4-initiated and cAMP-mediated abrogation of bacterial invasion of the bladder. Cell Host Microbe1:287-298.
    OpenUrlCrossRefPubMedWeb of Science
  244. 244.↵
    Song, J., B. L. Bishop, G. Li, R. Grady, A. Stapleton, and S. N. Abraham. 2009. TLR4-mediated expulsion of bacteria from infected bladder epithelial cells. Proc. Nat. Acad. Sci. U. S. A.106:14966-14971.
    OpenUrlAbstract/FREE Full Text
  245. 245.↵
    Song, J., M. J. Duncan, G. Li, C. Chan, R. Grady, A. Stapleton, and S. N. Abraham. 2007. A novel TLR4-mediated signaling pathway leading to IL-6 responses in human bladder epithelial cells. PLoS Pathog.3:e60.
    OpenUrlCrossRefPubMed
  246. 246.↵
    Sorensen, O. E., N. Borregaard, and A. M. Cole. 2008. Antimicrobial peptides in innate immune responses. Contrib. Microbiol.15:61-77.
    OpenUrlCrossRefPubMed
  247. 247.↵
    Springall, T., N. S. Sheerin, K. Abe, V. M. Holers, H. Wan, and S. H. Sacks. 2001. Epithelial secretion of C3 promotes colonization of the upper urinary tract by Escherichia coli. Nat. Med.7:801-806.
    OpenUrlCrossRefPubMedWeb of Science
  248. 248.↵
    Stuehr, D. J., S. S. Gross, I. Sakuma, R. Levi, and C. F. Nathan. 1989. Activated murine macrophages secrete a metabolite of arginine with the bioactivity of endothelium-derived relaxing factor and the chemical reactivity of nitric oxide. J. Exp. Med.169:1011-1020.
    OpenUrlAbstract/FREE Full Text
  249. 249.↵
    Svanborg-Eden, C., and A. M. Svennerholm. 1978. Secretory immunoglobulin A and G antibodies prevent adhesion of Escherichia coli to human urinary tract epithelial cells. Infect. Immun.22:790-797.
    OpenUrlAbstract/FREE Full Text
  250. 250.↵
    Svanborg Eden, C., D. Briles, L. Hagberg, J. McGhee, and S. Michalec. 1984. Genetic factors in host resistance to urinary tract infection. Infection12:118-123.
    OpenUrlCrossRefPubMedWeb of Science
  251. 251.↵
    Svensson, L., B. I. Marklund, M. Poljakovic, and K. Persson. 2006. Uropathogenic Escherichia coli and tolerance to nitric oxide: the role of flavohemoglobin. J. Urol.175:749-753.
    OpenUrlCrossRefPubMed
  252. 252.↵
    Tamm, I., and F. L. Horsfall, Jr. 1952. A mucoprotein derived from human urine which reacts with influenza, mumps, and Newcastle disease viruses. J. Exp. Med.95:71-97.
    OpenUrlAbstract/FREE Full Text
  253. 253.↵
    Tammen, H. 1990. Immunobiotherapy with Uro-Vaxom in recurrent urinary tract infection. The german urinary tract infection study group. Br. J. Urol.65:6-9.
    OpenUrlCrossRefPubMed
  254. 254.↵
    Tewari, R., T. Ikeda, R. Malaviya, J. I. MacGregor, J. R. Little, S. J. Hultgren, and S. N. Abraham. 1994. The PapG tip adhesin of P fimbriae protects Escherichia coli from neutrophil bactericidal activity. Infect. Immun.62:5296-5304.
    OpenUrlAbstract/FREE Full Text
  255. 255.↵
    Tezuka, H., Y. Abe, M. Iwata, H. Takeuchi, H. Ishikawa, M. Matsushita, T. Shiohara, S. Akira, and T. Ohteki. 2007. Regulation of IgA production by naturally occurring TNF/iNOS-producing dendritic cells. Nature448:929-933.
    OpenUrlCrossRefPubMedWeb of Science
  256. 256.↵
    Thankavel, K., B. Madison, T. Ikeda, R. Malaviya, A. H. Shah, P. M. Arumugam, and S. N. Abraham. 1997. Localization of a domain in the FimH adhesin of Escherichia coli type 1 fimbriae capable of receptor recognition and use of a domain-specific antibody to confer protection against experimental urinary tract infection. J. Clin. Invest.100:1123-1136.
    OpenUrlCrossRefPubMedWeb of Science
  257. 257.↵
    Thomas, W. E., L. M. Nilsson, M. Forero, E. V. Sokurenko, and V. Vogel. 2004. Shear-dependent “stick-and-roll” adhesion of type 1 fimbriated Escherichia coli. Mol. Microbiol.53:1545-1557.
    OpenUrlCrossRefPubMedWeb of Science
  258. 258.↵
    Thumbikat, P., R. E. Berry, A. J. Schaeffer, and D. J. Klumpp. 2009. Differentiation-induced uroplakin III expression promotes urothelial cell death in response to uropathogenic Escherichia coli. Microb. Infect.11:57-65.
    OpenUrlCrossRefPubMedWeb of Science
  259. 259.↵
    Thumbikat, P., R. E. Berry, G. Zhou, B. K. Billips, R. E. Yaggie, T. Zaichuk, T. T. Sun, A. J. Schaeffer, and D. J. Klumpp. 2009. Bacteria-induced uroplakin signaling mediates bladder response to infection. PLoS Pathog.5:e1000415.
    OpenUrlCrossRefPubMed
  260. 260.↵
    Thumbikat, P., C. Waltenbaugh, A. J. Schaeffer, and D. J. Klumpp. 2006. Antigen-specific responses accelerate bacterial clearance in the bladder. J. Immunol.176:3080-3086.
    OpenUrlAbstract/FREE Full Text
  261. 261.↵
    Tomasi, T. B., Jr., L. Larson, S. Challacombe, and P. McNabb. 1980. Mucosal immunity: the origin and migration patterns of cells in the secretory system. J. Allergy Clin. Immunol.65:12-19.
    OpenUrlCrossRefPubMed
  262. 262.↵
    Torchinsky, M. B., J. Garaude, A. P. Martin, and J. M. Blander. 2009. Innate immune recognition of infected apoptotic cells directs Th17 cell differentiation. Nature458:78-82.
    OpenUrlCrossRefPubMedWeb of Science
  263. 263.↵
    Trinchieri, A., L. Braceschi, D. Tiranti, S. Dell'Acqua, A. Mandressi, and E. Pisani. 1990. Secretory immunoglobulin A and inhibitory activity of bacterial adherence to epithelial cells in urine from patients with urinary tract infections. Urol. Res.18:305-308.
    OpenUrlCrossRefPubMed
  264. 264.↵
    Uehling, D. T., D. D. Barnhart, and C. V. Seastone. 1968. Antibody production in urinary bladder infection. Invest. Urol.6:211-222.
    OpenUrlPubMed
  265. 265.
    Uehling, D. T., W. J. Hopkins, and E. Balish. 1990. Decreased immunologic responsiveness following intensified vaginal immunization against urinary tract infection. J. Urol.143:143-145.
    OpenUrlPubMed
  266. 266.↵
    Uehling, D. T., W. J. Hopkins, E. Balish, Y. Xing, and D. M. Heisey. 1997. Vaginal mucosal immunization for recurrent urinary tract infection: phase II clinical trial. J. Urol.157:2049-2052.
    OpenUrlCrossRefPubMed
  267. 267.↵
    Uehling, D. T., W. J. Hopkins, L. M. Beierle, J. V. Kryger, and D. M. Heisey. 2001. Vaginal mucosal immunization for recurrent urinary tract infection: extended phase II clinical trial. J. Infect. Dis.183(Suppl. 1):S81-S83.
    OpenUrlCrossRefPubMed
  268. 268.
    Uehling, D. T., W. J. Hopkins, L. A. Dahmer, and E. Balish. 1994. Phase I clinical trial of vaginal mucosal immunization for recurrent urinary tract infection. J. Urol.152:2308-2311.
    OpenUrlPubMed
  269. 269.↵
    Uehling, D. T., W. J. Hopkins, J. E. Elkahwaji, D. M. Schmidt, and G. E. Leverson. 2003. Phase 2 clinical trial of a vaginal mucosal vaccine for urinary tract infections. J. Urol.170:867-869.
    OpenUrlCrossRefPubMedWeb of Science
  270. 270.↵
    Uehling, D. T., W. J. Hopkins, L. J. James, and E. Balish. 1994. Vaginal immunization of monkeys against urinary tract infection with a multi-strain vaccine. J. Urol.151:214-216.
    OpenUrlPubMedWeb of Science
  271. 271.
    Uehling, D. T., W. J. Hopkins, J. Jensen, and E. Balish. 1987. Vaginal immunization against induced cystitis in monkeys. J. Urol.137:327-329.
    OpenUrlPubMed
  272. 272.↵
    Uehling, D. T., L. J. James, W. J. Hopkins, and E. Balish. 1991. Immunization against urinary tract infection with a multi-valent vaginal vaccine. J. Urol.146:223-226.
    OpenUrlPubMed
  273. 273.
    Uehling, D. T., J. Jensen, and E. Balish. 1982. Vaginal immunization against urinary tract infection. J. Urol.128:1382-1384.
    OpenUrlPubMed
  274. 274.↵
    Uehling, D. T., K. Mizutani, and E. Balish. 1980. Inhibitors of bacterial adherence to urothelium. Invest. Urol.18:40-42.
    OpenUrlPubMed
  275. 275.↵
    Uehling, D. T., and L. Wolf. 1969. Enhancement of the bladder defense mechanism by immunization. Invest. Urol.6:520-526.
    OpenUrlPubMed
  276. 276.↵
    Valle, J., A. N. Mabbett, G. C. Ulett, A. Toledo-Arana, K. Wecker, M. Totsika, M. A. Schembri, J.-M. Ghigo, and C. Beloin. 2008. UpaG, a new member of the trimeric autotransporter family of adhesins in uropathogenic Escherichia coli. J. Bacteriol.190:4147-4161.
    OpenUrlAbstract/FREE Full Text
  277. 277.↵
    Valore, E. V., C. H. Park, A. J. Quayle, K. R. Wiles, P. B. McCray, Jr., and T. Ganz. 1998. Human beta-defensin-1: an antimicrobial peptide of urogenital tissues. J. Clin. Invest.101:1633-1642.
    OpenUrlCrossRefPubMedWeb of Science
  278. 278.↵
    Van Pham, T., B. Kreis, S. Corradin-Betz, J. Bauer, and J. Mauel. 1990. Metabolic and functional stimulation of lymphocytes and macrophages by an Escherichia coli extract (OM-89): in vitro studies. J. Biol. Response Mod.9:231-240.
    OpenUrlPubMed
  279. 279.↵
    Wally, J., and S. K. Buchanan. 2007. A structural comparison of human serum transferrin and human lactoferrin. Biometals20:249-262.
    OpenUrlCrossRefPubMed
  280. 280.↵
    Wang, C.-Y., M. W. Mayo, R. G. Korneluk, D. V. Goeddel, and A. S. Baldwin, Jr. 1998. NF-κB antiapoptosis: induction of TRAF1 and TRAF2 and c-IAP1 and c-IAP2 to suppress caspase-8 activation. Science281:1680-1683.
    OpenUrlAbstract/FREE Full Text
  281. 281.↵
    Wang, G., N. H. Moniri, K. Ozawa, J. S. Stamler, and Y. Daaka. 2006. Nitric oxide regulates endocytosis by S-nitrosylation of dynamin. Proc. Nat. Acad. Sci. U. S. A.103:1295-1300.
    OpenUrlAbstract/FREE Full Text
  282. 282.↵
    Warren, J. W. 1996. Clinical presentation and epidemiology of urinary tract infections, p. 3-27. In H. L. T. Mobley and J. W. Warren (ed.), Urinary tract infections: molecular pathogenesis and clinical management. ASM Press, Washington, DC.
  283. 283.↵
    Welch, R. A., V. Burland, G. Plunkett, 3rd, P. Redford, P. Roesch, D. Rasko, E. L. Buckles, S. R. Liou, A. Boutin, J. Hackett, D. Stroud, G. F. Mayhew, D. J. Rose, S. Zhou, D. C. Schwartz, N. T. Perna, H. L. Mobley, M. S. Donnenberg, and F. R. Blattner. 2002. Extensive mosaic structure revealed by the complete genome sequence of uropathogenic Escherichia coli. Proc. Natl. Acad. Sci. U. S. A.99:17020-17024.
    OpenUrlAbstract/FREE Full Text
  284. 284.↵
    Wiles, T. J., R. R. Kulesus, and M. A. Mulvey. 2008. Origins and virulence mechanisms of uropathogenic Escherichia coli. Exp. Mol. Pathol.85:11-19.
    OpenUrlCrossRefPubMedWeb of Science
  285. 285.↵
    Wright, K. J., P. C. Seed, and S. J. Hultgren. 2005. Uropathogenic Escherichia coli flagella aid in efficient urinary tract colonization. Infect. Immun.73:7657-7668.
    OpenUrlAbstract/FREE Full Text
  286. 286.↵
    Wu, X. R., T. T. Sun, and J. J. Medina. 1996. In vitro binding of type 1-fimbriated Escherichia coli to uroplakins Ia and Ib: relation to urinary tract infections. Proc. Nat. Acad. Sci. U. S. A.93:9630-9635.
    OpenUrlAbstract/FREE Full Text
  287. 287.↵
    Wullt, B., G. Bergsten, H. Connell, P. Rollano, N. Gebratsedik, L. Hang, and C. Svanborg. 2001. P-fimbriae trigger mucosal responses to Escherichia coli in the human urinary tract. Cell Microbiol.3:255-264.
    OpenUrlCrossRefPubMedWeb of Science
  288. 288.↵
    Wullt, B., G. Bergsten, H. Connell, P. Rollano, N. Gebretsadik, R. Hull, and C. Svanborg. 2000. P fimbriae enhance the early establishment of Escherichia coli in the human urinary tract. Mol. Microbiol.38:456-464.
    OpenUrlCrossRefPubMedWeb of Science
  289. 289.↵
    Wybran, J., M. Libin, and L. Schandene. 1989. Activation of natural killer cells and cytokine production in man by bacterial extracts. Immunopharmacol. Immunotoxicol.11:17-32.
    OpenUrlPubMed
  290. 290.↵
    Wybran, J., M. Libin, and L. Schandene. 1989. Enhancement of cytokine production and natural killer activity by an Escherichia coli extract. Onkologie12(Suppl. 3):22-25.
    OpenUrlPubMed
  291. 291.↵
    Yamamoto, S., T. Tsukamoto, A. Terai, H. Kurazono, Y. Takeda, and O. Yoshida. 1997. Genetic evidence supporting the fecal-perineal-urethral hypothesis in cystitis caused by Escherichia coli. Invest. Urol.157:1127-1129.
    OpenUrl
  292. 292.↵
    Yarovinsky, F., D. Zhang, J. F. Andersen, G. L. Bannenberg, C. N. Serhan, M. S. Hayden, S. Hieny, F. S. Sutterwala, R. A. Flavell, S. Ghosh, and A. Sher. 2005. TLR11 activation of dendritic cells by a protozoan profilin-like protein. Science308:1626-1629.
    OpenUrlAbstract/FREE Full Text
  293. 293.↵
    Zanetti, M. 2004. Cathelicidins, multifunctional peptides of the innate immunity. J. Leukoc. Biol.75:39-48.
    OpenUrlCrossRefPubMedWeb of Science
  294. 294.↵
    Zasloff, M. 2007. Antimicrobial peptides, innate immunity, and the normally sterile urinary tract. J. Am. Soc. Nephrol.18:2810-2816.
    OpenUrlAbstract/FREE Full Text
  295. 295.↵
    Zhang, A.-S., and C. A. Enns. 2009. Iron homeostasis: Recently identified proteins provide insight into novel control mechanisms. J. Biol. Chem.284:711-715.
    OpenUrlAbstract/FREE Full Text
  296. 296.↵
    Zhang, D., G. Zhang, M. S. Hayden, M. B. Greenblatt, C. Bussey, R. A. Flavell, and S. Ghosh. 2004. A toll-like receptor that prevents infection by uropathogenic bacteria. Science303:1522-1526.
    OpenUrlAbstract/FREE Full Text
  297. 297.↵
    Zhang, J. P., and S. Normark. 1996. Induction of gene expression in Escherichia coli after pilus-mediated adherence. Science273:1234-1236.
    OpenUrlAbstract
  298. 298.↵
    Zhou, G., W.-J. Mo, P. Sebbel, G. Min, T. A. Neubert, R. Glockshuber, X.-R. Wu, T.-T. Sun, and X.-P. Kong. 2001. Uroplakin Ia is the urothelial receptor for uropathogenic Escherichia coli: evidence from in vitro FimH binding. J. Cell Sci.114:4095-4103.
    OpenUrlPubMedWeb of Science

Author Bios

Embedded Image Kelsey E. Sivick was born and raised in eastern Pennsylvania, and she attended Penn State to attain her bachelor's degree in microbiology. She completed her undergraduate honors thesis research under the supervision of Sarah Ades, studying the extracytoplasmic stress factor σE in Escherichia coli. Moving on to study an E. coli strain of the uropathogenic pathotype in the lab of Harry Mobley, she earned her doctorate in microbiology and immunology at the University of Michigan in December 2009. She also graduated as a Cellular Biotechnology Training Program fellow, which provided her the opportunity to conduct vaccine research using a Listeria monocytogenes platform at the Cerus Corporation in Concord, CA. This position solidified her interest in research and host-pathogen interactions, which she will continue to pursue in her postdoctoral studies at the University of California—Berkeley.

Embedded Image Harry L. T. Mobley, a native of Louisville, Kentucky, received his B.S. degree in biology from Emory University in 1975 and his Ph.D. degree in microbiology and immunology from the University of Louisville in 1981. He conducted postdoctoral training in biological chemistry and then bacterial genetics in the Center for Vaccine Development at the University of Maryland School of Medicine, where he served on the faculty from 1984 until 2004. Dr. Mobley, a fellow in the American Academy of Microbiology, chaired the Pathogenesis and Host Response Mechanisms group of the American Society for Microbiology. He is a member of the editorial review boards of the journals Infection and Immunity and Helicobacter and has served as a study section member for the National Institutes of Health. In 2004, Dr. Mobley moved to the University of Michigan Medical School to serve as the Frederick G. Novy Professor and Chair of the Department of Microbiology and Immunology.

View Abstract
PreviousNext
Back to top
Download PDF
Citation Tools
Waging War against Uropathogenic Escherichia coli: Winning Back the Urinary Tract
Kelsey E. Sivick, Harry L. T. Mobley
Infection and Immunity Jan 2010, 78 (2) 568-585; DOI: 10.1128/IAI.01000-09

Citation Manager Formats

  • BibTeX
  • Bookends
  • EasyBib
  • EndNote (tagged)
  • EndNote 8 (xml)
  • Medlars
  • Mendeley
  • Papers
  • RefWorks Tagged
  • Ref Manager
  • RIS
  • Zotero
Print

Alerts
Sign In to Email Alerts with your Email Address
Email

Thank you for sharing this Infection and Immunity article.

NOTE: We request your email address only to inform the recipient that it was you who recommended this article, and that it is not junk mail. We do not retain these email addresses.

Enter multiple addresses on separate lines or separate them with commas.
Waging War against Uropathogenic Escherichia coli: Winning Back the Urinary Tract
(Your Name) has forwarded a page to you from Infection and Immunity
(Your Name) thought you would be interested in this article in Infection and Immunity.
CAPTCHA
This question is for testing whether or not you are a human visitor and to prevent automated spam submissions.
Share
Waging War against Uropathogenic Escherichia coli: Winning Back the Urinary Tract
Kelsey E. Sivick, Harry L. T. Mobley
Infection and Immunity Jan 2010, 78 (2) 568-585; DOI: 10.1128/IAI.01000-09
del.icio.us logo Digg logo Reddit logo Twitter logo CiteULike logo Facebook logo Google logo Mendeley logo
  • Top
  • Article
    • ABSTRACT
    • MISSION: ERADICATE UPEC-MEDIATED UTI
    • TERRAIN: THE URINARY TRACT
    • WEAPONS SYSTEMS: CURRENT AND PROPOSED TREATMENTS AND VACCINE INITIATIVES FOR UTI
    • TACTICAL DEFENSIVE MANEUVERS: HOST FACTORS TO PREVENT UPEC COLONIZATION
    • BATTLEFIELD INTELLIGENCE: HOST SIGNALING IN RESPONSE TO UPEC RECOGNITION
    • HAND-TO-HAND COMBAT: BATTLE FOR PRECIOUS RESOURCES
    • FRIENDLY FORCES: HOST FACTORS INVOLVED WITH INTRACELLULAR UPEC
    • CHEMICAL WARFARE: ANTIMICROBIAL PEPTIDES, CYTOKINES, AND CHEMOKINES
    • THE INFANTRY: NEUTROPHIL AND APC RESPONSES TO UPEC-MEDIATED UTI
    • SPECIAL OPERATIONS: ILLs IN THE INNATE IMMUNE RESPONSE TO UPEC-MEDIATED UTI
    • COVERT OPERATIONS: CELLULAR AND HUMORAL ADAPTIVE IMMUNE RESPONSES TO UPEC-MEDIATED UTI
    • RECONSTRUCTION AND RECOVERY: UROTHELIAL REGENERATION IN RESPONSE TO UPEC INFECTION
    • THE WAY AHEAD: VACCINE AND IMMUNIZATION STRATEGIES
    • REFERENCES
    • Author Bios
  • Figures & Data
  • Info & Metrics
  • PDF

KEYWORDS

Escherichia coli Infections
Urinary Tract Infections

Related Articles

Cited By...

About

  • About IAI
  • Editor in Chief
  • Editorial Board
  • Policies
  • For Reviewers
  • For the Media
  • For Librarians
  • For Advertisers
  • Alerts
  • RSS
  • FAQ
  • Permissions
  • Journal Announcements

Authors

  • ASM Author Center
  • Submit a Manuscript
  • Article Types
  • Ethics
  • Contact Us

Follow #IAIjournal

@ASMicrobiology

       

ASM Journals

ASM journals are the most prominent publications in the field, delivering up-to-date and authoritative coverage of both basic and clinical microbiology.

About ASM | Contact Us | Press Room

 

ASM is a member of

Scientific Society Publisher Alliance

 

American Society for Microbiology
1752 N St. NW
Washington, DC 20036
Phone: (202) 737-3600

Copyright © 2021 American Society for Microbiology | Privacy Policy | Website feedback

Print ISSN: 0019-9567; Online ISSN: 1098-5522