Minireview

Microbial Modulation of Host Immunity with the Small Molecule Phosphorylcholine

Sarah E. Clark, Jeffrey N. Weiser
A. T. Maurelli, Editor
DOI: 10.1128/IAI.01168-12

ABSTRACT

All microorganisms dependent on persistence in a host for survival rely on either hiding from or modulating host responses to infection. The small molecule phosphorylcholine, or choline phosphate (ChoP), is used for both of these purposes by a wide array of bacterial and parasitic microbes. While the mechanisms underlying ChoP acquisition and expression are diverse, a unifying theme is the use of ChoP to reduce the immune response to infection, creating an advantage for ChoP-expressing microorganisms. In this minireview, we discuss several benefits of ChoP expression during infection as well as how the immune system fights back against ChoP-expressing pathogens.

INTRODUCTION

Phosphorylcholine [(CH3)3N+CH2CH2PO4−] is a small (0.18-kDa) zwitterionic molecule expressed by a number of microbes across taxonomic kingdoms which infect humans and other eukaryotic hosts (1–4). Phosphorylcholine will be referred to here as ChoP, for choline phosphate. Most microbes that express ChoP acquire choline from their host. While choline is not required for growth in most prokaryotes, it is an essential nutrient in eukaryotes. Furthermore, choline is readily available to microbes during infection, as ChoP is a component of the most abundant eukaryotic membrane phospholipid, phosphatidylcholine. The turnover of phosphatidylcholine results in the release of glycerophospholipids containing choline (5). While microbes can use choline as a nutrient source (6) or as an osmoprotectant in the form of glycine betaine (7, 8), many also modify proteins or glycoconjugates with ChoP. ChoP may be either attached to the surface of the microbe or secreted on modified products.

The advantages of ChoP modification have been explored in both bacterial and parasitic systems. For extracellular bacteria that colonize the respiratory tract, where ChoP-expressing microbes are particularly common, ChoP is always attached to the bacterial surface (1, 9, 10). Surface expression of ChoP can affect epithelial cell adhesion and immune recognition. The intracellular bacterium Legionella pneumophila, in contrast, modifies a host protein with ChoP, aiding bacterial survival within host cells (11). In filarial nematodes, a secreted product that contains ChoP moderates the host inflammatory response, creating an environment amenable to parasite persistence (12). Despite the vast differences between these systems, a common theme is the use of ChoP to modulate the host response in order to support microbial survival.

The identification of ChoP on pathogenic microbes has led to the investigation of vaccine approaches to aid the recognition and clearance of ChoP-expressing pathogens. However, these efforts have been limited by the ability of ChoP to stimulate protective immunity, which is affected by the molecule to which it is attached as well as its accessibility within that molecule. The prevalence of ChoP expression, both in microbes and their host, demonstrates its importance in the constant interplay between these organisms. In this minireview, we discuss how bacteria and parasites use ChoP expression to promote survival in their respective hosts. Figure 1 summarizes the most-well-characterized pathways of ChoP-dependent host modulation during infection. The links between these different mechanisms may provide new avenues of investigation into the role of ChoP expression and how it can be targeted therapeutically.

Fig 1
Fig 1

Schematic of the mechanisms used by microbes to modulate host immune responses with phosphorylcholine. In bacteria such as S. pneumoniae, the attachment of ChoP to the bacterial surface allows for adhesion to the eukaryotic platelet-activating factor receptor (PAFr). This is an example of adhesion through molecular mimicry, in this case, mimicry of the natural PAFr-binding partner PAF, which also contains ChoP. In H. influenzae, ChoP expression reduces binding of bactericidal antibody. In L. pneumophila, the secreted protein AnkX attaches phosphorylcholine to host Rab1 GTPase in order to modify its activity. The secretion of ES-62 in nematodes results in ChoP-dependent inhibition of proinflammatory Th1 immunity.

MICROBIAL ACQUISITION AND EXPRESSION OF ChoP

Choline is an essential nutrient in humans, as it is required for the synthesis of several molecules, including cell membrane lipids, methionine, platelet-activating factor receptor, and the neurotransmitter acetylcholine (13). Choline turnover occurs continuously in eukaryotic cells during the synthesis and recycling of the major membrane lipid phosphatidylcholine (5). As a consequence, many microbes have adapted strategies to take advantage of host-accessible choline for use as a nutrient source, osmoprotectant, and mechanism for the evasion of host immune responses. The phosphorylated choline molecule ChoP is associated with a wide range of microorganisms. The two most well-characterized groups include bacterial species that colonize the upper respiratory tract and parasitic nematodes that secrete ChoP-modified products (9, 10, 14, 15). Importantly, ChoP is associated with commensal as well as pathogenic microbes. A summary of the microorganisms that express ChoP-modified molecules can be found in Table 1.

View this table:
Table 1

Microbes that use ChoP for structural modificationa

Choline is required for growth in some, but not all, bacterial species. The human respiratory pathogen Streptococcus pneumoniae, which cannot synthesize choline, is dependent on choline for growth (16). While S. pneumoniae can grow without choline in the presence of a choline structural analog, bacteria under these conditions form extended chains and are unable to autolyze or undergo transformation (17). When environmental choline is available, it is transported into the cell, transformed to ChoP, and incorporated into the cell wall teichoic acid (TA) or lipoteichoic acid (LTA) through the genes in the lic operon (18). The lic operon was first identified in another respiratory tract bacterial pathogen, Haemophilus influenzae, and is also present in commensal Neisseria strains (19, 20). The lic operon allows for molecular thievery, whereby microbes utilize a host resource to their own advantage. Parasites, in contrast, use the Kennedy pathway for phosphatidylcholine synthesis, similar to most eukaryotes (21–23). Some bacterial species can also synthesize phosphatidylcholine, either through the Kennedy pathway or by methylation of phosphatidylethanolamine, which is an alternative method for phosphatidylcholine synthesis also used by eukaryotes (24–26). Pathogenic Neisseria strains contain enzymes that are homologous to those used in the methylation pathway to synthesize ChoP (26).

Most microbes with ChoP-modified molecules have evolved mechanisms to vary ChoP expression and its location. In Pseudomonas aeruginosa, for example, ChoP is attached to the elongation factor Tu in a temperature-dependent manner (27). For S. pneumoniae, which attaches ChoP to the TA (cell wall) and LTA (cell membrane), the number of ChoP groups per cell wall repeating unit and the amount of TA itself are both variable (28, 29). Also, S. pneumoniae contains several choline-binding proteins which can attach to the ChoP-modified cell wall (30). While the choline-binding proteins of S. pneumoniae are diverse, from the cell wall hydrolytic enzyme LytA to the abundant surface molecule PspA, all have the potential to obscure antibody recognition of the ChoP epitope when bound to the pneumococcal cell wall (31, 32). In an S. pneumoniae PspA mutant, for example, there is increased binding of anti-ChoP antibodies as well as serum proteins that recognize ChoP (33).

The location of ChoP attachment itself is variable between different Neisseria species. In the pathogenic species Neisseria meningitidis and Neisseria gonorrhoeae, ChoP is covalently linked to serine residues on the bacterial pilus, while in commensal species, including Neisseria lactima and Neisseria subflava, it is found on the lipopolysaccharide (LPS) (20, 34). Pilus modification is a rare example of the direct attachment of ChoP to a protein residue as opposed to linkage through glycans, as for the majority of cases. ChoP attachment to the pilus in N. gonorrhoeae is in competition with attachment of phosphoethanolamine, and the “winner” is determined by the expression level of the protein PilV (34). In N. meningitidis, pilin modification is variable due to the presence of an unstable homopolymeric repeat in the ChoP transferase gene pptA (35). The on-off switching in expression due to the repeating sequence in pptA is an example of phase variation. ChoP attachment to the LPS in commensal Neisseria species and to the LPS in H. influenzae is also determined by phase variation.

Phase variation in commensal Neisseria spp. and H. influenzae is due to the presence of a track of tetranucleotide repeats in the first gene of the lic locus (19, 36). Phase variation in these bacteria occurs through slipped-strand mispairing, resulting in stochastic variation in ChoP attachment (37). Rather than controlling expression in response to an external stimulus, phase variation allows for rapid on-off switching of ChoP expression within the population. This strategy for regulation, or, rather, the absence of it, allows for the rapid selection of advantageous traits within a heterogeneous population exposed to new environments. In addition, there are multiple alleles of the ChoP transferase gene licD in H. influenzae strains. The licD allele carried by a given strain determines the location of attachment to the LPS (38). Finally, some strains of H. influenzae contain a duplication of the lic locus, resulting in the attachment of two ChoPs per LPS molecule (39).

Parasitic expression of the levels of several ChoP-modified molecules is also variable, albeit through different mechanisms than those found in bacterial species. While there is a range of different molecules modified by ChoP in Caenorhabditis elegans, stage-specific ChoP modification of glycosphingolipids occurs in this as well as other nematodes (40). For example, in the filarial nematode Acanthocheilonema viteae, ChoP is attached to the secretory product ES-62. Secretion of ES-62 is stage specific, restricted to the latest larval stage and adult worms, and occurs through posttranslational control of ES-62 production (41).

The acquisition and control of ChoP expression by so many diverse microorganisms allude to the importance of this small molecule. This is especially true during host infection, in which choline is readily available. Even the human host itself can undergo stage-specific modification of proteins with ChoP, such as during pregnancy. It has been shown that placental polypeptides are modified with ChoP, which has been proposed to help shield the fetus from immune recognition (42). In the following sections, the advantages and disadvantages of microbial ChoP expression in different host environments are highlighted.

ChoP AFFECTS HOST RECOGNITION

ChoP is found on the surface of several bacterial species, both commensal and pathogenic, that colonize the upper respiratory tract. Despite the constant phase variation of ChoP, ChoP-expressing phase variants of H. influenzae are the dominant population isolated from humans and from colonized mice (43–45). In a 6-day colonization study in healthy human adults, inoculation with mixed-phase-variant populations resulted in selection for ChoP-expressing phase variant-dominant populations following colonization (J. J. Poole, E. D. Foster, K. Chaloner, J. R. Hunt, M. P. Jennings, T. Bair, K. Knudtson, R. S. Munson, P. L. Winokur, E. S. Christensen, and M. A. Apicella, submitted for publication). While ChoP is important during colonization, it also plays a role during disease. For example, ChoP-expressing H. influenzae strains are more strongly associated with the development of otitis media in chinchillas (46). Correspondingly, ChoP-expressing H. influenzae strains are correlated with increased persistence in children with otitis media (47). H. influenzae strains expressing ChoP also have delayed clearance from the lungs of infected mice (48). ChoP expression is advantageous for other bacteria as well. S. pneumoniae strains without ChoP-modified TA are unable to colonize the upper respiratory tract in mice and are less virulent in a murine sepsis model (49). ChoP expression in Histophilus somni has also been shown to increase colonization of its bovine host (50).

One of the advantages of ChoP expression for survival in the respiratory tract is the ability of ChoP to increase bacterial adhesion to the epithelial cell surface. ChoP is part of the recognition domain of the host protein platelet-activating factor (PAF), which binds to host platelet-activating factor receptor (PAFr) on epithelial cells. Bacterial species, including H. influenzae, S. pneumoniae, Aggregatibacter actinomycetemcomitans, H. somni, P. aeruginosa, and commensal Neisseria strains, exhibit this version of molecular mimicry, allowing binding to PAFr in vitro (51–54). PAFr binding also increases cell invasion for several bacterial species, including S. pneumoniae, P. aeruginosa, A. actinomycetemcomitans, and Acinetobacter baumannii (27, 51, 52, 55). Invasion of epithelial cells allows bacteria to avoid extracellular immune responses, although intracellular survival is dependent on evasion of antibacterial intracellular immunity. Invasion of epithelial cells may also aid bacterial access to the bloodstream, exposing bacteria to yet another host environment. In support of a role for PAFr during bacterial infection, PAFr knockout mice are less susceptible to S. pneumoniae-induced pneumonia (56). S. pneumoniae also exhibits ChoP-dependent binding to the epithelial receptor asialo-GM1 (57). Although the mechanism for this binding remains unclear, this suggests that S. pneumoniae adheres to epithelial cells by binding multiple host receptors through ChoP. A role for ChoP in adhesion has also been proposed for some parasitic species. In the parasite Plasmodium falciparum, a Var family protein involved in parasite adhesion is modified with ChoP, although whether binding is dependent on ChoP has not been investigated (58). In contrast, a ChoP-modified glycoprotein in Dictyocaulus viviparus may inhibit, rather than aid, attachment to the host (59). While several bacterial species have increased adhesion to host cells through ChoP expression, this is not the only example of how ChoP contributes to microbial survival. Also, the in vivo impact of PAFr binding remains unclear for some species. For example, the role of PAFr is not always ChoP dependent, as PAFr has also been shown to be important in infection models with bacteria that do not express ChoP (60–62). In addition, there are examples of ChoP-expressing bacterial infections, such as colonization with H. influenzae, that are not affected by the absence of PAFr (63).

ChoP expression by microbes can also affect survival in the presence of host immune factors, including antibody, complement, and antimicrobial peptides. It was recently shown that ChoP expression in H. influenzae reduces antibody binding to the bacterial surface, resulting in increased survival in the presence of complement (64). ChoP attachment to the LPS in H. influenzae alters the physical properties of the outer membrane, resulting in decreased membrane accessibility, reduced membrane permeability, and an altered membrane melting temperature (64). ChoP expression in H. influenzae also increases resistance to antimicrobial peptides such as the human cathelicidin LL-37 (65). ChoP-expressing Pasteurella multocida strains are also more resistant to cathelicidins produced by their natural host, chickens (66). Increased resistance to antimicrobial peptides has been observed for other phosphorylated amine molecules, including phosphoethanolamine (PEtn) attached to lipopolysaccharide (LPS). When PEtn is expressed on lipid A or the LPS outer core, bacterial species, including Salmonella enterica and Citrobacter rodentium, have increased resistance to the antimicrobial peptide polymyxin B (67, 68). These effects may extend beyond LPS modification, as similar effects on polymyxin B sensitivity were also observed for PEtn attachment to flagella in Campylobacter jejuni (69). It is possible that phospho-amine-associated modifications serve to increase membrane stability in a number of bacterial strains, and the impact of these modifications on host recognition has only recently begun to be explored. ChoP-expressing H. influenzae strains are also associated with biofilms in vitro (70), and in a chinchilla model of otitis media, biofilm persistence was correlated with ChoP expression (71). While a cause-and-effect relationship between biofilms and ChoP expression in H. influenzae has not been established, these data suggest that ChoP-expressing phase variants have an advantage during biofilm establishment in the development of otitis media.

ChoP MODULATION OF THE HOST RESPONSE

In addition to altering host recognition, ChoP is used by microbes to modify host responses during infection. Recently, a mechanism for ChoP-dependent host modification was identified in the intracellular bacterium Legionella pneumophila. In this pathogen, a secreted protein reversibly phosphorylcholinates the host GTPase Rab1 (72). The bacterial secreted protein, AnkX, is a ChoP transferase, and ChoP modification of Rab1 results in host cell defects in endosome formation (11). It has been proposed that Legionella uses AnkX and the dephosphorylcholinase Lem3 as an alternative to the GTP/GDP exchange system used in human cells (73). It is possible that other intracellular bacteria use ChoP to modify the activity of host proteins, although whether this phenomenon is limited to the decoration of host GTPases is unclear. Alteration of endosome processing creates an advantage for L. pneumophila during intracellular survival, much as the increased epithelial cell adherence and reduced immune recognition aid extracellular bacteria during host colonization.

Microbes also use ChoP to modify the host immune response. Interestingly, all examples to date of ChoP-mediated immune modulation occur in parasites. However, there may be common links between the role of ChoP in parasites and its role in bacteria that have not yet been explored. The most thoroughly studied example of a ChoP-modified immunomodulatory molecule is ES-62, a secretory product of parasitic nematodes. Several of the immunomodulatory properties of ES-62 are dependent on the presence of ChoP. In A. viteae, ES-62 induces a Th2 immune response while reducing Th1 immunity. As part of the induction of a Th2-skewed immune response, macrophage and dendritic cell (DC) exposure to ES-62 reduces the production of interleukin 12 (IL-12) and tumor necrosis factor alpha (TNF-α) in response to classic inflammatory signals such as LPS (74). Also, exposure to ES-62 results in the maturation of dendritic cells that increase IL-4 and reduce gamma interferon (IFN-γ) cytokine production in T cells (75). ES-62 exposure additionally desensitizes B cell activation and proliferation through the traditional PI3K and Ras mitogen-activated protein (MAP) kinase signaling pathways (76, 77). Finally, ES-62 can induce a Th2-skewed antibody response, resulting in production of increased IgG1 and decreased IgG2a (78). The filarial nematode Brugia malayi also produces ChoP-modified antigens which suppress B and T cell signaling in a ChoP-dependent manner (79). The suppression of Th1 inflammation allows for parasite persistence within the host.

The phenotypes described above have also been replicated using the ChoP-conjugated OVA peptide. ChoP-OVA exposure alone results in the induction of Th2 immunity, demonstrating that ChoP is essential for the immune modulation observed during ES-62 exposure (80). Indeed, even the synthetic oxidized 1-palmitoyl-2-arachidonoyl-sn-glycero-3-phosphorylcholine, or oxPAPC, molecule, which contains ChoP, has been shown to bind TLR4 and induce IL-8 secretion (81). Interestingly, PAFr has been found on the surface of macrophages as well as B and T cells, raising the possibility that ChoP-mediated immune modulation occurs through PAFr binding (82, 83). However, while PAFr is functional on macrophages, it is not on B and T cells, suggesting the presence of additional immune activators responsible for ChoP-dependent effects on the immune system (84).

While the exposure or secretion of ChoP-modified molecules creates an advantage for microbes, the immune modulation that results also has the potential to affect immune homeostasis in the host. For example, the anti-inflammatory effect of ES-62 exposure also reduces arthritis in a ChoP-dependent manner (85). Additionally, the importance of ChoP-mediated effects on the immune response to concurrent or subsequent microbial infections remains to be explored.

HOST RESPONSES TO ChoP

Microbial expression of ChoP-modified molecules provides several potential advantages during host infection. However, the ability to vary ChoP expression in most microbes suggests that ChoP-modified molecules may be advantageous only in certain host environments. The acute-phase reactant protein C-reactive protein (CRP) recognizes ChoP and can initiate classical-pathway, complement-mediated killing of H. influenzae and increases phagocytosis of S. pneumoniae (43, 86). Even the position of ChoP on the LPS of H. influenzae affects the level of CRP-mediated bacterial killing (38). A role for CRP has also been demonstrated in vivo, as transgenic mice expressing human CRP have increased survival and reduced bacteremia following infection with S. pneumoniae, and the majority of these effects are dependent on complement (87, 88). Also, CRP binding to ChoP-modified pilin increases uptake of N. meningitidis by phagocytes (89). It was recently shown that in S. pneumoniae, CRP binding is inhibited by the surface protein PspA, which is anchored to ChoP (33). Inhibition of CRP binding also reduces complement deposition on the bacterial surface. CRP levels are initially low both in the blood and at the mucosal surface, although these increase dramatically during inflammation (90). When CRP is readily available, such as in rat or human serum during infection, ChoP-expressing H. influenzae strains are more sensitive to complement-mediated killing than bacteria not expressing ChoP (2, 91). In contrast, ChoP-expressing bacteria have the advantage in mouse and rabbit models of bloodstream infection, in which CRP levels remain low (92, 93). The pentraxin serum amyloid protein (SAP) can also bind ChoP, although no bactericidal effect has been demonstrated (94). Instead, SAP binding inhibits classical-pathway complement activity (95). The difference in the impact of CRP versus SAP binding highlights the concept that ChoP expression may be advantageous only in certain host conditions.

The second major host factor involved in ChoP recognition is the expression of anti-ChoP antibodies. Anti-ChoP antibodies are B1-lineage, natural antibodies. B1 antibodies are part of the repertoire of IgM synthesized prior to microbial exposure and have lower affinity than antibodies induced following infection (96). The major idiotype of anti-ChoP antibodies is T15, originally identified in mice (97, 98). While ChoP modification of host molecules, including the major cell membrane lipid phosphatidylcholine, is very common, it has been shown that T15 antibodies do not recognize the ChoP epitope in intact human membrane lipids (99, 100). Anti-ChoP antibodies do, however, recognize ChoP on intact or digested microbes, and it has been shown that there are detectable levels of circulating ChoP-containing antigens following infection with ChoP-expressing parasites in the bloodstream (101).

While anti-ChoP antibodies play a role in the recognition of microbes with ChoP-modified surfaces (102), they also are important during clearance of apoptotic cells and may be beneficial during atherosclerosis (103). As a case in point, anti-ChoP antibodies that bind to dental plaque bacteria cross-react with oxidized low-density lipoprotein (oxLDL), which contains ChoP (104). Reduced anti-ChoP IgM levels in patients with acute cardiovascular disease correspond with increased risk of a new cardiovascular event (105, 106). Also, higher anti-ChoP IgM levels correlate with decreased symptomology for systemic lupus erythematosus (SLE) patients (107). These effects, however, are not limited to anti-ChoP antibodies. CRP, known to play an important role in killing ChoP-expressing microbes, binds to oxLDL as well as apoptotic cells in a ChoP-dependent manner (108). However, ChoP-dependent recognition of LDL may not always be beneficial. A study investigating the effect of anti-ChoP antibodies on atherosclerosis found that opsonization of minimally modified LDL increased inflammation generated by DCs and NK cells (109). These studies suggest that infection with ChoP-expressing microbes can impact noninfectious-disease processes in the host.

Evasion of host recognition is critical for microbial survival during infection. However, microbes themselves are susceptible to infection, as exemplified by phage predation of bacteria. It has been shown that choline-modified TA in S. pneumoniae increases susceptibility to certain phages (110). Several pneumococcal phages contain proteins homologous to the cholin-binding proteins of S. pneumoniae, and choline-binding interactions have been demonstrated for some of these (111, 112). As LPS molecules can serve as phage receptors (113, 114), it is possible that ChoP attachment to the LPS affects phage susceptibility in other bacteria as well. In this way, ChoP expression may also impact intermicrobial competition in addition to the ongoing competition between microbe and host.

ChoP-BASED VACCINES

Vaccines that successfully stimulate a protective anti-ChoP response have the potential to be used for immunization against a wide range of ChoP-expressing microbes. Even though B1 anti-ChoP antibodies are low affinity, they provide some protection, as B1-deficient Xid mice (115) are more susceptible to S. pneumoniae infection (31). Beyond preexisting anti-ChoP B1 antibodies, stimulation of anti-ChoP antibody production occurs during exposure to ChoP-expressing microbes. Carriage of S. pneumoniae in young children is associated with increased levels of anti-ChoP antibodies (116). It remains unclear, however, whether these antibodies are able to protect children from additional infections with S. pneumoniae or other ChoP-expressing microbes.

While there is no vaccine currently in use that targets ChoP directly, there is one example of a licensed vaccine that induces a response against a protein involved in choline acquisition. One of the vaccines for S. pneumoniae contains 10 pneumococcal polysaccharide serotypes conjugated to protein D. Protein D is a glycerophodiester phosphodiesterase from H. influenzae that scavenges host choline (117). In children, the protein D-containing vaccine has 35% efficacy against otitis media caused by H. influenzae (118). Passive transfer of sera from children immunized with this vaccine protects chinchillas against H. influenzae otitis media with similar efficacy (119). The protein D-containing conjugate vaccine induces antibodies that inhibit the glpQ activity of protein D (120), suggesting that its efficacy is related to its ability to repress choline scavenging in vivo. In recent work, it was shown that abrogation of protein D activity results in reduced ChoP expression and decreased epithelial cell adherence and fitness in vivo (121). The success of the protein D-containing conjugate vaccine against H. influenzae infection, while limited, demonstrates the potential for targeting ChoP expression to protect against other ChoP-expressing microbes.

More direct approaches to target ChoP, such as inducing anti-ChoP antibodies, may have a greater impact on stimulating immunity to ChoP-expressing microbes. While the majority of ChoP-specific antibodies are IgM natural antibodies (122), human ChoP-specific IgG is protective against H. influenzae and S. pneumoniae in mouse models of infection (102). Patients with specific antibody defects, such as IgA-deficient patients, also have elevated levels of anti-ChoP IgG (123). Several vaccine formulations have demonstrated promise for the induction of ChoP-specific responses in animal models of infection with S. pneumoniae (124), N. meningitidis (125), and H. influenzae (126). In S. pneumoniae, the level of protection with anti-ChoP IgG is dependent on capsule type and the effectiveness of its shielding (127). ChoP vaccine formulations often involve conjugation of ChoP to a protein carrier, such as keyhole limpet hemocyanin (128, 129). ChoP is an example of a T cell-independent antigen, as with polysaccharides. Conjugation to a protein carrier allows for a repertoire shift in the anti-ChoP idiotype, resulting in the involvement of T cells and the development of higher-affinity antibodies (130). The induction of anti-ChoP antibodies may also provide protection against other ChoP-expressing bacteria, including A. actinomycetemcomitans and Treponema pallidum (131, 132). Interestingly, vaccination with S. pneumoniae induces T15 IgM that binds oxLDL, resulting in reduced atherosclerosis (133).

Targeting ChoP surface molecules is an attractive option as a strategy to immunize against multiple pathogens simultaneously. However, this would also affect ChoP-expressing commensal bacteria, and depletion of normal flora due to vaccination is a potential concern. Also, the variable expression of ChoP in many microbes suggests that even in the presence of protective anti-ChoP antibodies, phase variation or covering the ChoP epitope would allow infection to continue. Given the diversity in ChoP expression, additional targets may be required for vaccines against ChoP to have the most significant impact.

CONCLUDING REMARKS

The use of choline beyond a nutrient source has proven to be a useful strategy for microbes as a way to hide from (molecular mimicry) or alter host immune responses. The role of ChoP-modified molecules varies by microbe, although there may be undiscovered functional links. It is unclear, for example, whether ChoP-modified glycans or pilin in bacteria can modulate the immune response like ES-62 does during nematode infection. ChoP modulation of host immune responses may be dependent on the context in which it is presented. Additional studies should give insight into the development of ChoP-targeted vaccines and immune therapies using ChoP-modified molecules. Likewise, surface expression of ChoP on bacteria as demonstrated for H. influenzae may impact survival in the presence of antibody, complement, and antimicrobial peptides. ChoP itself may not be the only molecule capable of these and other effects, as other phospho-amine molecule modifications of the LPS increase resistance to antimicrobial peptides. Finally, there may be additional examples of related microbial products that can modify the activity of host proteins, as highlighted by the discovery of the ChoP transferase of L. pneumophila. Regardless of the interplay between different systems, the ability to manipulate ChoP has a marked effect on host recognition and response to microbes during infection.

There has been extensive interest in stimulating immune responses targeting ChoP-expressing microbes. However, the effects of anti-ChoP immunity also impact noninfectious-disease conditions, including arthritis, SLE, and atherosclerosis. There is clearly a dual role for anti-ChoP immune responses, which target ChoP-expressing microbes but also respond to host molecules with an exposed ChoP epitope, such as oxLDL. Even in the context of an effective anti-ChoP immune response, the seemingly universal capacity of microbes to vary either ChoP expression or accessibility limits the effectiveness of anti-ChoP immunity in eradicating infections. This minireview highlights ChoP as a key player in the constant battle between host and microbe during infection. The contribution of this dynamic molecule to microbial survival occurs through several different mechanisms, and the interplay between these and the host response to ChoP-expressing microbes is an important area for ongoing research.

REFERENCES

  1. 1.↵
    1. Fischer W,
    2. Behr T,
    3. Hartmann R,
    4. Peter-Katalinic J,
    5. Egge H
    . 1993. Teichoic acid and lipoteichoic acid of Streptococcus pneumoniae possess identical chain structures. A reinvestigation of teichoid acid (C polysaccharide). Eur. J. Biochem. 215:851–857.
    OpenUrlCrossRefPubMedWeb of Science
  2. 2.↵
    1. Weiser JN,
    2. Shchepetov M,
    3. Chong ST
    . 1997. Decoration of lipopolysaccharide with phosphorylcholine: a phase-variable characteristic of Haemophilus influenzae. Infect. Immun. 65:943–950.
    OpenUrlAbstract/FREE Full Text
  3. 3.↵
    1. Ben-Menachem G,
    2. Zahringer U,
    3. Rottem S
    . 2001. The phosphocholine motif in membranes of Mycoplasma fermentans strains. FEMS Microbiol. Lett. 199:137–141.
    OpenUrlCrossRefPubMedWeb of Science
  4. 4.↵
    1. Harnett W,
    2. Houston KM,
    3. Amess R,
    4. Worms MJ
    . 1993. Acanthocheilonema viteae: phosphorylcholine is attached to the major excretory-secretory product via an N-linked glycan. Exp. Parasitol. 77:498–502.
    OpenUrlCrossRefPubMedWeb of Science
  5. 5.↵
    1. Cabot MC,
    2. Welsh CJ,
    3. Cao HT,
    4. Chabbott H
    . 1988. The phosphatidylcholine pathway of diacylglycerol formation stimulated by phorbol diesters occurs via phospholipase D activation. FEBS Lett. 233:153–157.
    OpenUrlCrossRefPubMedWeb of Science
  6. 6.↵
    1. Salvano MA,
    2. Lisa TA,
    3. Domenech CE
    . 1989. Choline transport in Pseudomonas aeruginosa. Mol. Cell. Biochem. 85:81–89.
    OpenUrlPubMed
  7. 7.↵
    1. Fitzsimmons LF,
    2. Hampel KJ,
    3. Wargo MJ
    . 2012. Intracellular choline and glycine betaine pools impact osmoprotection and phospholipase C production in Pseudomonas aeruginosa. J. Bacteriol. 194:4718–4726.
    OpenUrlAbstract/FREE Full Text
  8. 8.↵
    1. Le Rudulier D,
    2. Strom AR,
    3. Dandekar AM,
    4. Smith LT,
    5. Valentine RC
    . 1984. Molecular biology of osmoregulation. Science 224:1064–1068.
    OpenUrlAbstract/FREE Full Text
  9. 9.↵
    1. Gillespie SH,
    2. Ainscough S,
    3. Dickens A,
    4. Lewin J
    . 1996. Phosphorylcholine-containing antigens in bacteria from the mouth and respiratory tract. J. Med. Microbiol. 44:35–40.
    OpenUrlCrossRefPubMedWeb of Science
  10. 10.↵
    1. Weiser JN,
    2. Goldberg JB,
    3. Pan N,
    4. Wilson L,
    5. Virji M
    . 1998. The phosphorylcholine epitope undergoes phase variation on a 43-kilodalton protein in Pseudomonas aeruginosa and on pili of Neisseria meningitidis and Neisseria gonorrhoeae. Infect. Immun. 66:4263–4267.
    OpenUrlAbstract/FREE Full Text
  11. 11.↵
    1. Mukherjee S,
    2. Liu X,
    3. Arasaki K,
    4. McDonough J,
    5. Galan JE,
    6. Roy CR
    . 2011. Modulation of Rab GTPase function by a protein phosphocholine transferase. Nature 477:103–106.
    OpenUrlCrossRefPubMedWeb of Science
  12. 12.↵
    1. Harnett W,
    2. Rzepecka J,
    3. Houston KM
    . 2010. How do nematodes transfer phosphorylcholine to carbohydrates? Trends Parasitol. 26:114–118.
    OpenUrlCrossRefPubMed
  13. 13.↵
    1. Zeisel SH
    . 2007. Gene response elements, genetic polymorphisms and epigenetics influence the human dietary requirement for choline. IUBMB Life 59:380–387.
    OpenUrlCrossRefPubMedWeb of Science
  14. 14.↵
    1. Gmur R,
    2. Thurnheer T,
    3. Guggenheim B
    . 1999. Dominant cross-reactive antibodies generated during the response to a variety of oral bacterial species detect phosphorylcholine. J. Dent. Res. 78:77–85.
    OpenUrlCrossRefPubMed
  15. 15.↵
    1. Houston KM,
    2. Harnett W
    . 2004. Structure and synthesis of nematode phosphorylcholine-containing glycoconjugates. Parasitology 129:655–661.
    OpenUrlCrossRefPubMedWeb of Science
  16. 16.↵
    1. Rane L,
    2. Subbarow Y
    . 1940. Nutritional requirements of the pneumococcus. 1. Growth factors for types I, II, V, VII, VIII. J. Bacteriol. 40:695–704.
    OpenUrlFREE Full Text
  17. 17.↵
    1. Tomasz A
    . 1968. Biological consequences of the replacement of choline by ethanolamine in the cell wall of Pneumococcus: chanin formation, loss of transformability, and loss of autolysis. Proc. Natl. Acad. Sci. U. S. A. 59:86–93.
    OpenUrlFREE Full Text
  18. 18.↵
    1. Zhang JR,
    2. Idanpaan-Heikkila I,
    3. Fischer W,
    4. Tuomanen EI
    . 1999. Pneumococcal licD2 gene is involved in phosphorylcholine metabolism. Mol. Microbiol. 31:1477–1488.
    OpenUrlCrossRefPubMedWeb of Science
  19. 19.↵
    1. Weiser JN,
    2. Lindberg AA,
    3. Manning EJ,
    4. Hansen EJ,
    5. Moxon ER
    . 1989. Identification of a chromosomal locus for expression of lipopolysaccharide epitopes in Haemophilus influenzae. Infect. Immun. 57:3045–3052.
    OpenUrlAbstract/FREE Full Text
  20. 20.↵
    1. Serino L,
    2. Virji M
    . 2000. Phosphorylcholine decoration of lipopolysaccharide differentiates commensal Neisseriae from pathogenic strains: identification of licA-type genes in commensal Neisseriae. Mol. Microbiol. 35:1550–1559.
    OpenUrlCrossRefPubMedWeb of Science
  21. 21.↵
    1. Sampels V,
    2. Hartmann A,
    3. Dietrich I,
    4. Coppens I,
    5. Sheiner L,
    6. Striepen B,
    7. Herrmann A,
    8. Lucius R,
    9. Gupta N
    . 2012. Conditional mutagenesis of a novel choline kinase demonstrates plasticity of phosphatidylcholine biogenesis and gene expression in Toxoplasma gondii. J. Biol. Chem. 287:16289–16299.
    OpenUrlAbstract/FREE Full Text
  22. 22.↵
    1. Braker JD,
    2. Hodel KJ,
    3. Mullins DR,
    4. Friesen JA
    . 2009. Identification of hydrophobic amino acids required for lipid activation of C. elegans CTP:phosphocholine cytidylyltransferase. Arch. Biochem. Biophys. 492:10–16.
    OpenUrlCrossRefPubMed
  23. 23.↵
    1. Houston KM,
    2. Harnett W
    . 1999. Mechanisms underlying the transfer of phosphorylcholine to filarial nematode glycoproteins—a possible role for choline kinase. Parasitology 118(Part 3):311–318.
    OpenUrlCrossRefPubMed
  24. 24.↵
    1. Arondel V,
    2. Benning C,
    3. Somerville CR
    . 1993. Isolation and functional expression in Escherichia coli of a gene encoding phosphatidylethanolamine methyltransferase (EC 2.1.1.17) from Rhodobacter sphaeroides. J. Biol. Chem. 268:16002–16008.
    OpenUrlAbstract/FREE Full Text
  25. 25.↵
    1. Lopez-Lara IM,
    2. Geiger O
    . 2001. Novel pathway for phosphatidylcholine biosynthesis in bacteria associated with eukaryotes. J. Biotechnol. 91:211–221.
    OpenUrlCrossRefPubMedWeb of Science
  26. 26.↵
    1. Aas FE,
    2. Egge-Jacobsen W,
    3. Winther-Larsen HC,
    4. Lovold C,
    5. Hitchen PG,
    6. Dell A,
    7. Koomey M
    . 2006. Neisseria gonorrhoeae type IV pili undergo multisite, hierarchical modifications with phosphoethanolamine and phosphocholine requiring an enzyme structurally related to lipopolysaccharide phosphoethanolamine transferases. J. Biol. Chem. 281:27712–27723.
    OpenUrlAbstract/FREE Full Text
  27. 27.↵
    1. Barbier M,
    2. Oliver A,
    3. Rao J,
    4. Hanna SL,
    5. Goldberg JB,
    6. Alberti S
    . 2008. Novel phosphorylcholine-containing protein of Pseudomonas aeruginosa chronic infection isolates interacts with airway epithelial cells. J. Infect. Dis. 197:465–473.
    OpenUrlCrossRefPubMed
  28. 28.↵
    1. Kim JO,
    2. Weiser JN
    . 1998. Association of intrastrain phase variation in quantity of capsular polysaccharide and teichoic acid with the virulence of Streptococcus pneumoniae. J. Infect. Dis. 177:368–377.
    OpenUrlCrossRefPubMedWeb of Science
  29. 29.↵
    1. Karlsson C,
    2. Jansson PE,
    3. Skov Sorensen UB
    . 1999. The pneumococcal common antigen C-polysaccharide occurs in different forms. Mono-substituted or di-substituted with phosphocholine. Eur. J. Biochem. 265:1091–1097.
    OpenUrlCrossRefPubMedWeb of Science
  30. 30.↵
    1. Hakenbeck R,
    2. Madhour A,
    3. Denapaite D,
    4. Bruckner R
    . 2009. Versatility of choline metabolism and choline-binding proteins in Streptococcus pneumoniae and commensal streptococci. FEMS Microbiol. Rev. 33:572–586.
    OpenUrlCrossRefPubMed
  31. 31.↵
    1. Yother J,
    2. Forman C,
    3. Gray BM,
    4. Briles DE
    . 1982. Protection of mice from infection with Streptococcus pneumoniae by anti-phosphocholine antibody. Infect. Immun. 36:184–188.
    OpenUrlAbstract/FREE Full Text
  32. 32.↵
    1. Sanchez-Puelles JM,
    2. Ronda C,
    3. Garcia JL,
    4. Garcia P,
    5. Lopez R,
    6. Garcia E
    . 1986. Searching for autolysin functions. Characterization of a pneumococcal mutant deleted in the lytA gene. Eur. J. Biochem. 158:289–293.
    OpenUrlPubMedWeb of Science
  33. 33.↵
    1. Mukerji M,
    2. Mirza S,
    3. Roche AM,
    4. Widener RW,
    5. Rhee D-K,
    6. Weiser JN,
    7. Szalai AJ,
    8. Briles DE
    . 2012. Pneumococcal surface protein A (PspA) inhibits complement deposition on the pneumococcal surface by competing with the binding of C-reactive protein (CRP) to cell-surface phosphorylcholine. J. Immunol. 189:5327–5335.
    OpenUrlAbstract/FREE Full Text
  34. 34.↵
    1. Hegge FT,
    2. Hitchen PG,
    3. Aas FE,
    4. Kristiansen H,
    5. Lovold C,
    6. Egge-Jacobsen W,
    7. Panico M,
    8. Leong WY,
    9. Bull Virji VM,
    10. Morris HR,
    11. Dell A,
    12. Koomey M
    . 2004. Unique modifications with phosphocholine and phosphoethanolamine define alternate antigenic forms of Neisseria gonorrhoeae type IV pili. Proc. Natl. Acad. Sci. U. S. A. 101:10798–10803.
    OpenUrlAbstract/FREE Full Text
  35. 35.↵
    1. Warren MJ,
    2. Jennings MP
    . 2003. Identification and characterization of pptA: a gene involved in the phase-variable expression of phosphorylcholine on pili of Neisseria meningitidis. Infect. Immun. 71:6892–6898.
    OpenUrlAbstract/FREE Full Text
  36. 36.↵
    1. Weiser JN,
    2. Love JM,
    3. Moxon ER
    . 1989. The molecular mechanism of phase variation of H. influenzae lipopolysaccharide. Cell 59:657–665.
    OpenUrlCrossRefPubMedWeb of Science
  37. 37.↵
    1. Henderson IR,
    2. Owen P,
    3. Nataro JP
    . 1999. Molecular switches—the ON and OFF of bacterial phase variation. Mol. Microbiol. 33:919–932.
    OpenUrlCrossRefPubMedWeb of Science
  38. 38.↵
    1. Lysenko E,
    2. Richards JC,
    3. Cox AD,
    4. Stewart A,
    5. Martin A,
    6. Kapoor M,
    7. Weiser JN
    . 2000. The position of phosphorylcholine on the lipopolysaccharide of Haemophilus influenzae affects binding and sensitivity to C-reactive protein-mediated killing. Mol. Microbiol. 35:234–245.
    OpenUrlCrossRefPubMedWeb of Science
  39. 39.↵
    1. Fox KL,
    2. Li J,
    3. Schweda EK,
    4. Vitiazeva V,
    5. Makepeace K,
    6. Jennings MP,
    7. Moxon ER,
    8. Hood DW
    . 2008. Duplicate copies of lic1 direct the addition of multiple phosphocholine residues in the lipopolysaccharide of Haemophilus influenzae. Infect. Immun. 76:588–600.
    OpenUrlAbstract/FREE Full Text
  40. 40.↵
    1. Lochnit G,
    2. Grabitzki J,
    3. Henkel B,
    4. Tavernarakis N,
    5. Geyer R
    . 2006. First identification of a phosphorylcholine-substituted protein from Caenorhabditis elegans: isolation and characterization of the aspartyl protease ASP-6. Biol. Chem. 387:1487–1493.
    OpenUrlPubMed
  41. 41.↵
    1. Stepek G,
    2. Auchie M,
    3. Tate R,
    4. Watson K,
    5. Russell DG,
    6. Devaney E,
    7. Harnett W
    . 2002. Expression of the filarial nematode phosphorylcholine-containing glycoprotein, ES62, is stage specific. Parasitology 125:155–164.
    OpenUrlPubMed
  42. 42.↵
    1. Lovell TM,
    2. Woods RJ,
    3. Butlin DJ,
    4. Brayley KJ,
    5. Manyonda IT,
    6. Jarvis J,
    7. Howell S,
    8. Lowry PJ
    . 2007. Identification of a novel mammalian post-translational modification, phosphocholine, on placental secretory polypeptides. J. Mol. Endocrinol. 39:189–198.
    OpenUrlAbstract/FREE Full Text
  43. 43.↵
    1. Weiser JN,
    2. Pan N
    . 1998. Adaptation of Haemophilus influenzae to acquired and innate humoral immunity based on phase variation of lipopolysaccharide. Mol. Microbiol. 30:767–775.
    OpenUrlCrossRefPubMedWeb of Science
  44. 44.↵
    1. Marti-Lliteras P,
    2. Lopez-Gomez A,
    3. Mauro S,
    4. Hood DW,
    5. Viadas C,
    6. Calatayud L,
    7. Morey P,
    8. Servin A,
    9. Linares J,
    10. Oliver A,
    11. Bengoechea JA,
    12. Garmendia J
    . 2011. Nontypable Haemophilus influenzae displays a prevalent surface structure molecular pattern in clinical isolates. PLoS One 6:e21133. doi:10.1371/journal.pone.0021133.
    OpenUrlCrossRefPubMed
  45. 45.↵
    1. Weiser JN,
    2. Pan N,
    3. McGowan KL,
    4. Musher D,
    5. Martin A,
    6. Richards J
    . 1998. Phosphorylcholine on the lipopolysaccharide of Haemophilus influenzae contributes to persistence in the respiratory tract and sensitivity to serum killing mediated by C-reactive protein. J. Exp. Med. 187:631–640.
    OpenUrlAbstract/FREE Full Text
  46. 46.↵
    1. Tong HH,
    2. Blue LE,
    3. James MA,
    4. Chen YP,
    5. DeMaria TF
    . 2000. Evaluation of phase variation of nontypeable Haemophilus influenzae lipooligosaccharide during nasopharyngeal colonization and development of otitis media in the chinchilla model. Infect. Immun. 68:4593–4597.
    OpenUrlAbstract/FREE Full Text
  47. 47.↵
    1. Fujita K,
    2. Hirano T,
    3. Kodama S,
    4. Suzuki M
    . 2009. Prognostic impact of phosphorylcholine expression in nontypeable Haemophilus influenzae in otitis media with effusion. Acta Otolaryngol. 129:832–838.
    OpenUrlCrossRefPubMed
  48. 48.↵
    1. Pang B,
    2. Winn D,
    3. Johnson R,
    4. Hong W,
    5. West-Barnette S,
    6. Kock N,
    7. Swords WE
    . 2008. Lipooligosaccharides containing phosphorylcholine delay pulmonary clearance of nontypeable Haemophilus influenzae. Infect. Immun. 76:2037–2043.
    OpenUrlAbstract/FREE Full Text
  49. 49.↵
    1. Kharat AS,
    2. Tomasz A
    . 2006. Drastic reduction in the virulence of Streptococcus pneumoniae expressing type 2 capsular polysaccharide but lacking choline residues in the cell wall. Mol. Microbiol. 60:93–107.
    OpenUrlCrossRefPubMed
  50. 50.↵
    1. Elswaifi SF,
    2. Scarratt WF,
    3. Inzana TJ
    . 2012. The role of lipooligosaccharide phosphorylcholine in colonization and pathogenesis of Histophilus somni in cattle. Vet. Res. 43:49.
    OpenUrlCrossRefPubMed
  51. 51.↵
    1. Cundell DR,
    2. Gerard NP,
    3. Gerard C,
    4. Idanpaan-Heikkila I,
    5. Tuomanen EI
    . 1995. Streptococcus pneumoniae anchor to activated human cells by the receptor for platelet-activating factor. Nature 377:435–438.
    OpenUrlCrossRefPubMedWeb of Science
  52. 52.↵
    1. Schenkein HA,
    2. Barbour SE,
    3. Berry CR,
    4. Kipps B,
    5. Tew JG
    . 2000. Invasion of human vascular endothelial cells by Actinobacillus actinomycetemcomitans via the receptor for platelet-activating factor. Infect. Immun. 68:5416–5419.
    OpenUrlAbstract/FREE Full Text
  53. 53.↵
    1. Swords WE,
    2. Buscher BA,
    3. Ver Steeg Ii K,
    4. Preston A,
    5. Nichols WA,
    6. Weiser JN,
    7. Gibson BW,
    8. Apicella MA
    . 2000. Non-typeable Haemophilus influenzae adhere to and invade human bronchial epithelial cells via an interaction of lipooligosaccharide with the PAF receptor. Mol. Microbiol. 37:13–27.
    OpenUrlCrossRefPubMedWeb of Science
  54. 54.↵
    1. Serino L,
    2. Virji M
    . 2002. Genetic and functional analysis of the phosphorylcholine moiety of commensal Neisseria lipopolysaccharide. Mol. Microbiol. 43:437–448.
    OpenUrlCrossRefPubMed
  55. 55.↵
    1. Smani Y,
    2. Docobo-Perez F,
    3. Lopez-Rojas R,
    4. Dominguez-Herrera J,
    5. Ibanez-Martinez J,
    6. Pachon J
    . 2012. Platelet-activating factor receptor initiates Acinetobacter baumannii expressing phosphorylcholine contact with host cells. J. Biol. Chem. 287:26901–26910.
    OpenUrlAbstract/FREE Full Text
  56. 56.↵
    1. Rijneveld AW,
    2. Weijer S,
    3. Florquin S,
    4. Speelman P,
    5. Shimizu T,
    6. Ishii S,
    7. van der Poll T
    . 2004. Improved host defense against pneumococcal pneumonia in platelet-activating factor receptor-deficient mice. J. Infect. Dis. 189:711–716.
    OpenUrlCrossRefPubMedWeb of Science
  57. 57.↵
    1. Sundberg-Kovamees M,
    2. Holme T,
    3. Sjogren A
    . 1996. Interaction of the C-polysaccharide of Streptococcus pneumoniae with the receptor asialo-GM1. Microb. Pathog. 21:223–234.
    OpenUrlCrossRefPubMedWeb of Science
  58. 58.↵
    1. Grabitzki J,
    2. Lochnit G
    . 2009. Immunomodulation by phosphocholine—biosynthesis, structures and immunological implications of parasitic PC-epitopes. Mol. Immunol. 47:149–163.
    OpenUrlCrossRefPubMed
  59. 59.↵
    1. Kooyman FN,
    2. van Balkom BW,
    3. de Vries E,
    4. van Putten JP
    . 2009. Identification of a thrombospondin-like immunodominant and phosphorylcholine-containing glycoprotein (GP300) in Dictyocaulus viviparus and related nematodes. Mol. Biochem. Parasitol. 163:85–94.
    OpenUrlCrossRefPubMed
  60. 60.↵
    1. Soares AC,
    2. Pinho VS,
    3. Souza DG,
    4. Shimizu T,
    5. Ishii S,
    6. Nicoli JR,
    7. Teixeira MM
    . 2002. Role of the platelet-activating factor (PAF) receptor during pulmonary infection with gram negative bacteria. Br. J. Pharmacol. 137:621–628.
    OpenUrlCrossRefPubMedWeb of Science
  61. 61.↵
    1. Hosoki K,
    2. Nakamura A,
    3. Nagao M,
    4. Hiraguchi Y,
    5. Tanida H,
    6. Tokuda R,
    7. Wada H,
    8. Nobori T,
    9. Suga S,
    10. Fujisawa T
    . 2012. Staphylococcus aureus directly activates eosinophils via platelet-activating factor receptor. J. Leukoc. Biol. 92:333–341.
    OpenUrlCrossRefPubMedWeb of Science
  62. 62.↵
    1. Fonteles M,
    2. Fang G,
    3. Thielman NM,
    4. Yotseff PS,
    5. Guerrant RL
    . 1995. Role of platelet activating factor in the inflammatory and secretory effects of Clostridium difficile toxin A. J. Lipid Mediat. Cell Signal. 11:133–143.
    OpenUrlCrossRefPubMed
  63. 63.↵
    1. Branger J,
    2. Wieland CW,
    3. Florquin S,
    4. Maris NA,
    5. Pater JM,
    6. Speelman P,
    7. Shimizu T,
    8. Ishii S,
    9. van der Poll T
    . 2004. Platelet-activating factor receptor-deficient mice show an unaltered clearance of nontypeable Haemophilus influenzae from their respiratory tract. Shock 22:543–547.
    OpenUrlCrossRefPubMed
  64. 64.↵
    1. Clark SE,
    2. Snow J,
    3. Li J,
    4. Zola TA,
    5. Weiser JN
    . 2012. Phosphorylcholine allows for evasion of bactericidal antibody by Haemophilus influenzae. PLoS Pathog. 8:e1002521. doi:10.1371/journal.ppat.1002521.
    OpenUrlCrossRefPubMed
  65. 65.↵
    1. Lysenko ES,
    2. Gould J,
    3. Bals R,
    4. Wilson JM,
    5. Weiser JN
    . 2000. Bacterial phosphorylcholine decreases susceptibility to the antimicrobial peptide LL-37/hCAP18 expressed in the upper respiratory tract. Infect. Immun. 68:1664–1671.
    OpenUrlAbstract/FREE Full Text
  66. 66.↵
    1. Harper M,
    2. Cox A,
    3. St Michael F,
    4. Parnas H,
    5. Wilkie I,
    6. Blackall PJ,
    7. Adler B,
    8. Boyce JD
    . 2007. Decoration of Pasteurella multocida lipopolysaccharide with phosphocholine is important for virulence. J. Bacteriol. 189:7384–7391.
    OpenUrlAbstract/FREE Full Text
  67. 67.↵
    1. Murata T,
    2. Tseng W,
    3. Guina T,
    4. Miller SI,
    5. Nikaido H
    . 2007. PhoPQ-mediated regulation produces a more robust permeability barrier in the outer membrane of Salmonella enterica serovar Typhimurium. J. Bacteriol. 189:7213–7222.
    OpenUrlAbstract/FREE Full Text
  68. 68.↵
    1. Viau C,
    2. Le Sage V,
    3. Ting DK,
    4. Gross J,
    5. Le Moual H
    . 2011. Absence of PmrAB-mediated phosphoethanolamine modifications of Citrobacter rodentium lipopolysaccharide affects outer membrane integrity. J. Bacteriol. 193:2168–2176.
    OpenUrlAbstract/FREE Full Text
  69. 69.↵
    1. Cullen TW,
    2. Trent MS
    . 2010. A link between the assembly of flagella and lipooligosaccharide of the Gram-negative bacterium Campylobacter jejuni. Proc. Natl. Acad. Sci. U. S. A. 107:5160–5165.
    OpenUrlAbstract/FREE Full Text
  70. 70.↵
    1. West-Barnette S,
    2. Rockel A,
    3. Swords WE
    . 2006. Biofilm growth increases phosphorylcholine content and decreases potency of nontypeable Haemophilus influenzae endotoxins. Infect. Immun. 74:1828–1836.
    OpenUrlAbstract/FREE Full Text
  71. 71.↵
    1. Hong W,
    2. Mason K,
    3. Jurcisek J,
    4. Novotny L,
    5. Bakaletz LO,
    6. Swords WE
    . 2007. Phosphorylcholine decreases early inflammation and promotes the establishment of stable biofilm communities of nontypeable Haemophilus influenzae strain 86-028NP in a chinchilla model of otitis media. Infect. Immun. 75:958–965.
    OpenUrlAbstract/FREE Full Text
  72. 72.↵
    1. Tan Y,
    2. Arnold RJ,
    3. Luo ZQ
    . 2011. Legionella pneumophila regulates the small GTPase Rab1 activity by reversible phosphorylcholination. Proc. Natl. Acad. Sci. U. S. A. 108:21212–21217.
    OpenUrlAbstract/FREE Full Text
  73. 73.↵
    1. Goody PR,
    2. Heller K,
    3. Oesterlin LK,
    4. Muller MP,
    5. Itzen A,
    6. Goody RS
    . 2012. Reversible phosphocholination of Rab proteins by Legionella pneumophila effector proteins. EMBO J. 31:1774–1784.
    OpenUrlCrossRefPubMedWeb of Science
  74. 74.↵
    1. Goodridge HS,
    2. Marshall FA,
    3. Else KJ,
    4. Houston KM,
    5. Egan C,
    6. Al-Riyami L,
    7. Liew FY,
    8. Harnett W,
    9. Harnett MM
    . 2005. Immunomodulation via novel use of TLR4 by the filarial nematode phosphorylcholine-containing secreted product, ES-62. J. Immunol. 174:284–293.
    OpenUrlAbstract/FREE Full Text
  75. 75.↵
    1. Whelan M,
    2. Harnett MM,
    3. Houston KM,
    4. Patel V,
    5. Harnett W,
    6. Rigley KP
    . 2000. A filarial nematode-secreted product signals dendritic cells to acquire a phenotype that drives development of Th2 cells. J. Immunol. 164:6453–6460.
    OpenUrlAbstract/FREE Full Text
  76. 76.↵
    1. Deehan MR,
    2. Frame MJ,
    3. Parkhouse RM,
    4. Seatter SD,
    5. Reid SD,
    6. Harnett MM,
    7. Harnett W
    . 1998. A phosphorylcholine-containing filarial nematode-secreted product disrupts B lymphocyte activation by targeting key proliferative signaling pathways. J. Immunol. 160:2692–2699.
    OpenUrlAbstract/FREE Full Text
  77. 77.↵
    1. Harnett W,
    2. Harnett MM
    . 1993. Inhibition of murine B cell proliferation and down-regulation of protein kinase C levels by a phosphorylcholine-containing filarial excretory-secretory product. J. Immunol. 151:4829–4837.
    OpenUrlAbstract/FREE Full Text
  78. 78.↵
    1. Marshall FA,
    2. Grierson AM,
    3. Garside P,
    4. Harnett W,
    5. Harnett MM
    . 2005. ES-62, an immunomodulator secreted by filarial nematodes, suppresses clonal expansion and modifies effector function of heterologous antigen-specific T cells in vivo. J. Immunol. 175:5817–5826.
    OpenUrlAbstract/FREE Full Text
  79. 79.↵
    1. Lal RB,
    2. Kumaraswami V,
    3. Steel C,
    4. Nutman TB
    . 1990. Phosphocholine-containing antigens of Brugia malayi nonspecifically suppress lymphocyte function. Am. J. Trop. Med. Hyg. 42:56–64.
    OpenUrlAbstract/FREE Full Text
  80. 80.↵
    1. Goodridge HS,
    2. McGuiness S,
    3. Houston KM,
    4. Egan CA,
    5. Al-Riyami L,
    6. Alcocer MJ,
    7. Harnett MM,
    8. Harnett W
    . 2007. Phosphorylcholine mimics the effects of ES-62 on macrophages and dendritic cells. Parasite Immunol. 29:127–137.
    OpenUrlCrossRefPubMedWeb of Science
  81. 81.↵
    1. Walton KA,
    2. Hsieh X,
    3. Gharavi N,
    4. Wang S,
    5. Wang G,
    6. Yeh M,
    7. Cole AL,
    8. Berliner JA
    . 2003. Receptors involved in the oxidized 1-palmitoyl-2-arachidonoyl-sn-glycero-3-phosphorylcholine-mediated synthesis of interleukin-8. A role for Toll-like receptor 4 and a glycosylphosphatidylinositol-anchored protein. J. Biol. Chem. 278:29661–29666.
    OpenUrlAbstract/FREE Full Text
  82. 82.↵
    1. Nguer CM,
    2. Pellegrini O,
    3. Galanaud P,
    4. Benveniste J,
    5. Thomas Y,
    6. Richard Y
    . 1992. Regulation of paf-acether receptor expression in human B cells. J. Immunol. 149:2742–2748.
    OpenUrlAbstract
  83. 83.↵
    1. Calabresse C,
    2. Nguer MC,
    3. Pellegrini O,
    4. Benveniste J,
    5. Richard Y,
    6. Thomas Y
    . 1992. Induction of high-affinity paf receptor expression during T cell activation. Eur. J. Immunol. 22:1349–1355.
    OpenUrlPubMed
  84. 84.↵
    1. Simon HU,
    2. Tsao PW,
    3. Siminovitch KA,
    4. Mills GB,
    5. Blaser K
    . 1994. Functional platelet-activating factor receptors are expressed by monocytes and granulocytes but not by resting or activated T and B lymphocytes from normal individuals or patients with asthma. J. Immunol. 153:364–377.
    OpenUrlAbstract
  85. 85.↵
    1. Harnett MM,
    2. Kean DE,
    3. Boitelle A,
    4. McGuiness S,
    5. Thalhamer T,
    6. Steiger CN,
    7. Egan C,
    8. Al-Riyami L,
    9. Alcocer MJ,
    10. Houston KM,
    11. Gracie JA,
    12. McInnes IB,
    13. Harnett W
    . 2008. The phosphorycholine moiety of the filarial nematode immunomodulator ES-62 is responsible for its anti-inflammatory action in arthritis. Ann. Rheum. Dis. 67:518–523.
    OpenUrlAbstract/FREE Full Text
  86. 86.↵
    1. Mold C,
    2. Du Clos TW,
    3. Nakayama S,
    4. Edwards KM,
    5. Gewurz H
    . 1982. C-reactive protein reactivity with complement and effects on phagocytosis. Ann. N. Y. Acad. Sci. 389:251–262.
    OpenUrlCrossRefPubMed
  87. 87.↵
    1. Szalai AJ,
    2. Briles DE,
    3. Volanakis JE
    . 1995. Human C-reactive protein is protective against fatal Streptococcus pneumoniae infection in transgenic mice. J. Immunol. 155:2557–2563.
    OpenUrlAbstract
  88. 88.↵
    1. Szalai AJ,
    2. Briles DE,
    3. Volanakis JE
    . 1996. Role of complement in C-reactive-protein-mediated protection of mice from Streptococcus pneumoniae. Infect. Immun. 64:4850–4853.
    OpenUrlAbstract/FREE Full Text
  89. 89.↵
    1. Casey R,
    2. Newcombe J,
    3. McFadden J,
    4. Bodman-Smith KB
    . 2008. The acute-phase reactant C-reactive protein binds to phosphorylcholine-expressing Neisseria meningitidis and increases uptake by human phagocytes. Infect. Immun. 76:1298–1304.
    OpenUrlAbstract/FREE Full Text
  90. 90.↵
    1. Gould JM,
    2. Weiser JN
    . 2001. Expression of C-reactive protein in the human respiratory tract. Infect. Immun. 69:1747–1754.
    OpenUrlAbstract/FREE Full Text
  91. 91.↵
    1. Humphries HE,
    2. High NJ
    . 2002. The role of licA phase variation in the pathogenesis of invasive disease by Haemophilus influenzae type b. FEMS Immunol. Med. Microbiol. 34:221–230.
    OpenUrlCrossRefPubMedWeb of Science
  92. 92.↵
    1. Erwin AL,
    2. Brewah YA,
    3. Couchenour DA,
    4. Barren PR,
    5. Burke SJ,
    6. Choi GH,
    7. Lathigra R,
    8. Hanson MS,
    9. Weiser JN
    . 2000. Role of lipopolysaccharide phase variation in susceptibility of Haemophilus influenzae to bactericidal immunoglobulin M antibodies in rabbit sera. Infect. Immun. 68:2804–2807.
    OpenUrlAbstract/FREE Full Text
  93. 93.↵
    1. Gehre F,
    2. Spisek R,
    3. Kharat AS,
    4. Matthews P,
    5. Kukreja A,
    6. Anthony RM,
    7. Dhodapkar MV,
    8. Vollmer W,
    9. Tomasz A
    . 2009. Role of teichoic acid choline moieties in the virulence of Streptococcus pneumoniae. Infect. Immun. 77:2824–2831.
    OpenUrlAbstract/FREE Full Text
  94. 94.↵
    1. Christner RB,
    2. Mortensen RF
    . 1994. Binding of human serum amyloid P-component to phosphocholine. Arch. Biochem. Biophys. 314:337–343.
    OpenUrlCrossRefPubMedWeb of Science
  95. 95.↵
    1. de Haas CJ,
    2. van Leeuwen EM,
    3. van Bommel T,
    4. Verhoef J,
    5. van Kessel KP,
    6. van Strijp JA
    . 2000. Serum amyloid P component bound to gram-negative bacteria prevents lipopolysaccharide-mediated classical pathway complement activation. Infect. Immun. 68:1753–1759.
    OpenUrlAbstract/FREE Full Text
  96. 96.↵
    1. Baumgarth N,
    2. Tung JW,
    3. Herzenberg LA
    . 2005. Inherent specificities in natural antibodies: a key to immune defense against pathogen invasion. Springer Semin. Immunopathol. 26:347–362.
    OpenUrlCrossRefPubMedWeb of Science
  97. 97.↵
    1. Lieberman R,
    2. Potter M,
    3. Mushinski EB,
    4. Humphrey W Jr,
    5. Rudikoff S
    . 1974. Genetics of a new IgVH (T15 idiotype) marker in the mouse regulating natural antibody to phosphorylcholine. J. Exp. Med. 139:983–1001.
    OpenUrlAbstract
  98. 98.↵
    1. Kenny JJ,
    2. Moratz CM,
    3. Guelde G,
    4. O'Connell CD,
    5. George J,
    6. Dell C,
    7. Penner SJ,
    8. Weber JS,
    9. Berry J,
    10. Claflin JL,
    11. Longo DL
    . 1992. Antigen binding and idiotype analysis of antibodies obtained after electroporation of heavy and light chain genes encoding phosphocholine-specific antibodies: a model for T15-idiotype dominance. J. Exp. Med. 176:1637–1643.
    OpenUrlAbstract/FREE Full Text
  99. 99.↵
    1. Urbaneja MA,
    2. Chapman D
    . 1989. The binding of phosphorylcholine-carrying antigens to the anti-phosphorylcholine monoclonal antibody TEPC 15. A fluorescence spectroscopic study. Biochim. Biophys. Acta 998:85–90.
    OpenUrlCrossRefPubMed
  100. 100.↵
    1. Cox KO,
    2. Hardy SJ
    . 1985. Autoantibodies against mouse bromelain-modified RBC are specifically inhibited by a common membrane phospholipid, phosphatidylcholine. Immunology 55:263–269.
    OpenUrlPubMedWeb of Science
  101. 101.↵
    1. Lal RB,
    2. Ottesen EA
    . 1989. Phosphocholine epitopes on helminth and protozoal parasites and their presence in the circulation of infected human patients. Trans. R. Soc. Trop. Med. Hyg. 83:652–655.
    OpenUrlCrossRefPubMed
  102. 102.↵
    1. Goldenberg HB,
    2. McCool TL,
    3. Weiser JN
    . 2004. Cross-reactivity of human immunoglobulin G2 recognizing phosphorylcholine and evidence for protection against major bacterial pathogens of the human respiratory tract. J. Infect. Dis. 190:1254–1263.
    OpenUrlCrossRefPubMedWeb of Science
  103. 103.↵
    1. Shaw PX,
    2. Horkko S,
    3. Chang MK,
    4. Curtiss LK,
    5. Palinski W,
    6. Silverman GJ,
    7. Witztum JL
    . 2000. Natural antibodies with the T15 idiotype may act in atherosclerosis, apoptotic clearance, and protective immunity. J. Clin. Invest. 105:1731–1740.
    OpenUrlCrossRefPubMedWeb of Science
  104. 104.↵
    1. Schenkein HA,
    2. Berry CR,
    3. Purkall D,
    4. Burmeister JA,
    5. Brooks CN,
    6. Tew JG
    . 2001. Phosphorylcholine-dependent cross-reactivity between dental plaque bacteria and oxidized low-density lipoproteins. Infect. Immun. 69:6612–6617.
    OpenUrlAbstract/FREE Full Text
  105. 105.↵
    1. Caidahl K,
    2. Hartford M,
    3. Karlsson T,
    4. Herlitz J,
    5. Pettersson K,
    6. de Faire U,
    7. Frostegard J
    . 6 February 2012. IgM-phosphorylcholine autoantibodies and outcome in acute coronary syndromes. Int. J. Cardiol. doi:10.1016/j.ijcard.2012.01.018.
  106. 106.↵
    1. Fiskesund R,
    2. Stegmayr B,
    3. Hallmans G,
    4. Vikstrom M,
    5. Weinehall L,
    6. de Faire U,
    7. Frostegard J
    . 2010. Low levels of antibodies against phosphorylcholine predict development of stroke in a population-based study from northern Sweden. Stroke 41:607–612.
    OpenUrlAbstract/FREE Full Text
  107. 107.↵
    1. Gronwall C,
    2. Akhter E,
    3. Oh C,
    4. Burlingame RW,
    5. Petri M,
    6. Silverman GJ
    . 2012. IgM autoantibodies to distinct apoptosis-associated antigens correlate with protection from cardiovascular events and renal disease in patients with SLE. Clin. Immunol. 142:390–398.
    OpenUrlCrossRefPubMed
  108. 108.↵
    1. Chang MK,
    2. Binder CJ,
    3. Torzewski M,
    4. Witztum JL
    . 2002. C-reactive protein binds to both oxidized LDL and apoptotic cells through recognition of a common ligand: phosphorylcholine of oxidized phospholipids. Proc. Natl. Acad. Sci. U. S. A. 99:13043–13048.
    OpenUrlAbstract/FREE Full Text
  109. 109.↵
    1. Kikuchi T,
    2. El Shikh MM,
    3. El Sayed RM,
    4. Purkall DB,
    5. Elaasser MM,
    6. Sarraf A,
    7. Barbour SE,
    8. Schenkein HA,
    9. Tew JG
    . 2010. Anti-phosphorylcholine-opsonized low-density lipoprotein promotes rapid production of proinflammatory cytokines by dendritic cells and natural killer cells. J. Periodontal Res. 45:720–730.
    OpenUrlCrossRefPubMed
  110. 110.↵
    1. Lopez R,
    2. Garcia E,
    3. Garcia P,
    4. Ronda C,
    5. Tomasz A
    . 1982. Choline-containing bacteriophage receptors in Streptococcus pneumoniae. J. Bacteriol. 151:1581–1590.
    OpenUrlAbstract/FREE Full Text
  111. 111.↵
    1. Hermoso JA,
    2. Monterroso B,
    3. Albert A,
    4. Galan B,
    5. Ahrazem O,
    6. Garcia P,
    7. Martinez-Ripoll M,
    8. Garcia JL,
    9. Menendez M
    . 2003. Structural basis for selective recognition of pneumococcal cell wall by modular endolysin from phage Cp-1. Structure 11:1239–1249.
    OpenUrlCrossRefPubMed
  112. 112.↵
    1. Saiz JL,
    2. Lopez-Zumel C,
    3. Monterroso B,
    4. Varea J,
    5. Arrondo JL,
    6. Iloro I,
    7. Garcia JL,
    8. Laynez J,
    9. Menendez M
    . 2002. Characterization of Ejl, the cell-wall amidase coded by the pneumococcal bacteriophage Ej-1. Protein Sci. 11:1788–1799.
    OpenUrlCrossRefPubMedWeb of Science
  113. 113.↵
    1. Yokota S,
    2. Hayashi T,
    3. Matsumoto H
    . 1994. Identification of the lipopolysaccharide core region as the receptor site for a cytotoxin-converting phage, ϕCTX, of Pseudomonas aeruginosa. J. Bacteriol. 176:5262–5269.
    OpenUrlAbstract/FREE Full Text
  114. 114.↵
    1. Inagaki M,
    2. Tanaka A,
    3. Suzuki R,
    4. Wakashima H,
    5. Kawaura T,
    6. Karita S,
    7. Nishikawa S,
    8. Kashimura N
    . 2000. Characterization of the binding of spike H protein of bacteriophage phiX174 with receptor lipopolysaccharides. J. Biochem. 127:577–583.
    OpenUrlCrossRefPubMedWeb of Science
  115. 115.↵
    1. Satterthwaite AB,
    2. Li Z,
    3. Witte ON
    . 1998. Btk function in B cell development and response. Semin. Immunol. 10:309–316.
    OpenUrlCrossRefPubMedWeb of Science
  116. 116.↵
    1. Gray BM,
    2. Dillon HC Jr,
    3. Briles DE
    . 1983. Epidemiological studies of Streptococcus pneumoniae in infants: development of antibody to phosphocholine. J. Clin. Microbiol. 18:1102–1107.
    OpenUrlAbstract/FREE Full Text
  117. 117.↵
    1. Munson RS Jr,
    2. Sasaki K
    . 1993. Protein D, a putative immunoglobulin D-binding protein produced by Haemophilus influenzae, is glycerophosphodiester phosphodiesterase. J. Bacteriol. 175:4569–4571.
    OpenUrlAbstract/FREE Full Text
  118. 118.↵
    1. Prymula R,
    2. Peeters P,
    3. Chrobok V,
    4. Kriz P,
    5. Novakova E,
    6. Kaliskova E,
    7. Kohl I,
    8. Lommel P,
    9. Poolman J,
    10. Prieels JP,
    11. Schuerman L
    . 2006. Pneumococcal capsular polysaccharides conjugated to protein D for prevention of acute otitis media caused by both Streptococcus pneumoniae and non-typable Haemophilus influenzae: a randomised double-blind efficacy study. Lancet 367:740–748.
    OpenUrlCrossRefPubMedWeb of Science
  119. 119.↵
    1. Novotny LA,
    2. Jurcisek JA,
    3. Godfroid F,
    4. Poolman JT,
    5. Denoel PA,
    6. Bakaletz LO
    . 2006. Passive immunization with human anti-protein D antibodies induced by polysaccharide protein D conjugates protects chinchillas against otitis media after intranasal challenge with Haemophilus influenzae. Vaccine 24:4804–4811.
    OpenUrlCrossRefPubMedWeb of Science
  120. 120.↵
    1. Toropainen M,
    2. Raitolehto A,
    3. Henckaerts I,
    4. Wauters D,
    5. Poolman J,
    6. Lestrate P,
    7. Kayhty H
    . 2008. Pneumococcal Haemophilus influenzae protein D conjugate vaccine induces antibodies that inhibit glycerophosphodiester phosphodiesterase activity of protein D. Infect. Immun. 76:4546–4553.
    OpenUrlAbstract/FREE Full Text
  121. 121.↵
    1. Johnson RW,
    2. McGillivary G,
    3. Denoel P,
    4. Poolman J,
    5. Bakaletz LO
    . 2011. Abrogation of nontypeable Haemophilus influenzae Protein D function reduces phosphorylcholine decoration, adherence to airway epithelial cells, and fitness in a chinchilla model of otitis media. Vaccine 29:1211–1221.
    OpenUrlCrossRefPubMedWeb of Science
  122. 122.↵
    1. Sigal NH,
    2. Gearhart PJ,
    3. Klinman NR
    . 1975. The frequency of phosphorylcholine-specific B cells in conventional and germfree BALB/C mice. J. Immunol. 114:1354–1358.
    OpenUrlAbstract/FREE Full Text
  123. 123.↵
    1. Fusaro AE,
    2. Fahl K,
    3. Cardoso EC,
    4. de Brito CA,
    5. Jacob CM,
    6. Carneiro-Sampaio M,
    7. Duarte AJ,
    8. Sato MN
    . 2010. Profile of autoantibodies against phosphorylcholine and cross-reactivity to oxidation-specific neoantigens in selective IgA deficiency with or without autoimmune diseases. J. Clin. Immunol. 30:872–880.
    OpenUrlCrossRefPubMed
  124. 124.↵
    1. Trolle S,
    2. Chachaty E,
    3. Kassis-Chikhani N,
    4. Wang C,
    5. Fattal E,
    6. Couvreur P,
    7. Diamond B,
    8. Alonso J,
    9. Andremont A
    . 2000. Intranasal immunization with protein-linked phosphorylcholine protects mice against a lethal intranasal challenge with Streptococcus pneumoniae. Vaccine 18:2991–2998.
    OpenUrlCrossRefPubMed
  125. 125.↵
    1. Bay S,
    2. Huteau V,
    3. Zarantonelli ML,
    4. Pires R,
    5. Ughetto-Monfrin J,
    6. Taha MK,
    7. England P,
    8. Lafaye P
    . 2004. Phosphorylcholine-carbohydrate-protein conjugates efficiently induce hapten-specific antibodies which recognize both Streptococcus pneumoniae and Neisseria meningitidis: a potential multitarget vaccine against respiratory infections. J. Med. Chem. 47:3916–3919.
    OpenUrlCrossRefPubMed
  126. 126.↵
    1. Tanaka N,
    2. Fukuyama S,
    3. Fukuiwa T,
    4. Kawabata M,
    5. Sagara Y,
    6. Ito HO,
    7. Miwa Y,
    8. Nagatake T,
    9. Kiyono H,
    10. Kurono Y
    . 2007. Intranasal immunization with phosphorylcholine induces antigen specific mucosal and systemic immune responses in mice. Vaccine 25:2680–2687.
    OpenUrlCrossRefPubMed
  127. 127.↵
    1. Briles DE,
    2. Forman C,
    3. Crain M
    . 1992. Mouse antibody to phosphocholine can protect mice from infection with mouse-virulent human isolates of Streptococcus pneumoniae. Infect. Immun. 60:1957–1962.
    OpenUrlAbstract/FREE Full Text
  128. 128.↵
    1. Fischer RT,
    2. Longo DL,
    3. Kenny JJ
    . 1995. A novel phosphocholine antigen protects both normal and X-linked immune deficient mice against Streptococcus pneumoniae. Comparison of the 6-O-phosphocholine hydroxyhexanoate-conjugate with other phosphocholine-containing vaccines. J. Immunol. 154:3373–3382.
    OpenUrlAbstract
  129. 129.↵
    1. Baatarjav T,
    2. Kataoka K,
    3. Gilbert RS,
    4. Terao Y,
    5. Fukui M,
    6. Goto M,
    7. Kawabata S,
    8. Yamamoto M,
    9. Fujihashi K,
    10. Ito HO
    . 2011. Mucosal immune features to phosphorylcholine by nasal Flt3 ligand cDNA-based vaccination. Vaccine 29:5747–5757.
    OpenUrlCrossRefPubMed
  130. 130.↵
    1. Brown M,
    2. Schumacher MA,
    3. Wiens GD,
    4. Brennan RG,
    5. Rittenberg MB
    . 2000. The structural basis of repertoire shift in an immune response to phosphocholine. J. Exp. Med. 191:2101–2112.
    OpenUrlAbstract/FREE Full Text
  131. 131.↵
    1. Purkall D,
    2. Tew JG,
    3. Schenkein HA
    . 2002. Opsonization of Actinobacillus actinomycetemcomitans by immunoglobulin G antibody reactive with phosphorylcholine. Infect. Immun. 70:6485–6488.
    OpenUrlAbstract/FREE Full Text
  132. 132.↵
    1. Blanco DR,
    2. Champion CI,
    3. Dooley A,
    4. Cox DL,
    5. Whitelegge JP,
    6. Faull K,
    7. Lovett MA
    . 2005. A monoclonal antibody that conveys in vitro killing and partial protection in experimental syphilis binds a phosphorylcholine surface epitope of Treponema pallidum. Infect. Immun. 73:3083–3095.
    OpenUrlAbstract/FREE Full Text
  133. 133.↵
    1. Binder CJ,
    2. Horkko S,
    3. Dewan A,
    4. Chang MK,
    5. Kieu EP,
    6. Goodyear CS,
    7. Shaw PX,
    8. Palinski W,
    9. Witztum JL,
    10. Silverman GJ
    . 2003. Pneumococcal vaccination decreases atherosclerotic lesion formation: molecular mimicry between Streptococcus pneumoniae and oxidized LDL. Nat. Med. 9:736–743.
    OpenUrlCrossRefPubMedWeb of Science
  134. 134.
    1. Gillespie SH,
    2. McWhinney PH,
    3. Patel S,
    4. Raynes JG,
    5. McAdam KP,
    6. Whiley RA,
    7. Hardie JM
    . 1993. Species of alpha-hemolytic streptococci possessing a C-polysaccharide phosphorylcholine-containing antigen. Infect. Immun. 61:3076–3077.
    OpenUrlAbstract/FREE Full Text
  135. 135.
    1. McCrea KW,
    2. Xie J,
    3. Marrs CF,
    4. Gilsdorf JR
    . 2010. Prevalence of genetic differences in phosphorylcholine expression between nontypeable Haemophilus influenzae and Haemophilus haemolyticus. BMC Microbiol. 10:286.
    OpenUrlCrossRefPubMed
  136. 136.
    1. Cox AD,
    2. Howard MD,
    3. Brisson JR,
    4. van der Zwan M,
    5. Thibault P,
    6. Perry MB,
    7. Inzana TJ
    . 1998. Structural analysis of the phase-variable lipooligosaccharide from Haemophilus somnus strain 738. Eur. J. Biochem. 253:507–516.
    OpenUrlPubMed
  137. 137.
    1. St Michael F,
    2. Li J,
    3. Vinogradov E,
    4. Larocque S,
    5. Harper M,
    6. Cox AD
    . 2005. Structural analysis of the lipopolysaccharide of Pasteurella multocida strain VP161: identification of both Kdo-P and Kdo-Kdo species in the lipopolysaccharide. Carbohydr. Res. 340:59–68.
    OpenUrlCrossRefPubMedWeb of Science
  138. 138.
    1. Fudala R,
    2. Kondakova AN,
    3. Bednarska K,
    4. Senchenkova SN,
    5. Shashkov AS,
    6. Knirel YA,
    7. Zahringer U,
    8. Kaca W
    . 2003. Structure and serological characterization of the O-antigen of Proteus mirabilis O18 with a phosphocholine-containing oligosaccharide phosphate repeating unit. Carbohydr. Res. 338:1835–1842.
    OpenUrlCrossRefPubMed
  139. 139.
    1. Young NM,
    2. Kreisman LS,
    3. Stupak J,
    4. MacLean LL,
    5. Cobb BA,
    6. Richards JC
    . 2011. Structural characterization and MHCII-dependent immunological properties of the zwitterionic O-chain antigen of Morganella morganii. Glycobiology 21:1266–1276.
    OpenUrlCrossRefPubMed
  140. 140.
    1. Gerdt S,
    2. Dennis RD,
    3. Borgonie G,
    4. Schnabel R,
    5. Geyer R
    . 1999. Isolation, characterization and immunolocalization of phosphorylcholine-substituted glycolipids in developmental stages of Caenorhabditis elegans. Eur. J. Biochem. 266:952–963.
    OpenUrlPubMedWeb of Science
  141. 141.
    1. Maizels RM,
    2. Burke J,
    3. Denham DA
    . 1987. Phosphorylcholine-bearing antigens in filarial nematode parasites: analysis of somatic extracts, in-vitro secretions and infection sera from Brugia malayi and B. pahangi. Parasite Immunol. 9:49–66.
    OpenUrlCrossRefPubMedWeb of Science
  142. 142.
    1. Hewitson JP,
    2. Harcus YM,
    3. Curwen RS,
    4. Dowle AA,
    5. Atmadja AK,
    6. Ashton PD,
    7. Wilson A,
    8. Maizels RM
    . 2008. The secretome of the filarial parasite, Brugia malayi: proteomic profile of adult excretory-secretory products. Mol. Biochem. Parasitol. 160:8–21.
    OpenUrlCrossRefPubMedWeb of Science
  143. 143.
    1. Lochnit G,
    2. Dennis RD,
    3. Ulmer AJ,
    4. Geyer R
    . 1998. Structural elucidation and monokine-inducing activity of two biologically active zwitterionic glycosphingolipids derived from the porcine parasitic nematode Ascaris suum. J. Biol. Chem. 273:466–474.
    OpenUrlAbstract/FREE Full Text
  144. 144.
    1. van Riet E,
    2. Wuhrer M,
    3. Wahyuni S,
    4. Retra K,
    5. Deelder AM,
    6. Tielens AG,
    7. van der Kleij D,
    8. Yazdanbakhsh M
    . 2006. Antibody responses to Ascaris-derived proteins and glycolipids: the role of phosphorylcholine. Parasite Immunol. 28:363–371.
    OpenUrlCrossRefPubMed
  145. 145.
    1. Wuhrer M,
    2. Rickhoff S,
    3. Dennis RD,
    4. Lochnit G,
    5. Soboslay PT,
    6. Baumeister S,
    7. Geyer R
    . 2000. Phosphocholine-containing, zwitterionic glycosphingolipids of adult Onchocerca volvulus as highly conserved antigenic structures of parasitic nematodes. Biochem. J. 348(Part 2):417–423.
    OpenUrlAbstract/FREE Full Text
  146. 146.
    1. Haslam SM,
    2. Houston KM,
    3. Harnett W,
    4. Reason AJ,
    5. Morris HR,
    6. Dell A
    . 1999. Structural studies of N-glycans of filarial parasites. Conservation of phosphorylcholine-substituted glycans among species and discovery of novel chito-oligomers. J. Biol. Chem. 274:20953–20960.
    OpenUrlAbstract/FREE Full Text
  147. 147.
    1. Lim PL,
    2. Choy WF
    . 1990. A thymus-independent (type 1) phosphorylcholine antigen isolated from Trichinella spiralis protects mice against pneumococcal infection. Immunology 69:443–448.
    OpenUrlPubMed
  148. 148.
    1. Morelle W,
    2. Haslam SM,
    3. Olivier V,
    4. Appleton JA,
    5. Morris HR,
    6. Dell A
    . 2000. Phosphorylcholine-containing N-glycans of Trichinella spiralis: identification of multiantennary lacdiNAc structures. Glycobiology 10:941–950.
    OpenUrlCrossRefPubMedWeb of Science
  149. 149.
    1. Pery P,
    2. Luffau G,
    3. Charley J,
    4. Petit A,
    5. Rouze P,
    6. Bernard S
    . 1979. Phosphorylcholine antigens from Nippostrongylus brasiliensis. II. Isolation and partial characterization of phosphorylcholine antigens from adult worm. Ann. Immunol. (Paris) 130:889–900.
    OpenUrlPubMed
  150. 150.
    1. Day KP,
    2. Spark R,
    3. Garner P,
    4. Raiko A,
    5. Wenger JD,
    6. Weiss N,
    7. Mitchell GF,
    8. Alpers MP,
    9. Kazura JW
    . 1991. Serological evaluation of the macrofilaricidal effects of diethylcarbamazine treatment in bancroftian filariasis. Am. J. Trop. Med. Hyg. 44:528–535.
    OpenUrlAbstract/FREE Full Text
  151. 151.
    1. Heise A,
    2. Peters W,
    3. Zahner H
    . 1999. Phosphocholine epitopes in Eimeria bovis. Exp. Parasitol. 92:279–282.
    OpenUrlCrossRefPubMed
Back to top
Download PDF
Citation Tools
Print

Alerts
Email

Related Articles

Cited By...