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Infection and Immunity, August 2007, p. 4082-4087, Vol. 75, No. 8
0019-9567/07/$08.00+0     doi:10.1128/IAI.00474-07
Copyright © 2007, American Society for Microbiology. All Rights Reserved.

Factor H Binding to PspC of Streptococcus pneumoniae Increases Adherence to Human Cell Lines In Vitro and Enhances Invasion of Mouse Lungs In Vivo

Lisa R. Quin,¹ Chinwendu Onwubiko,¹ Quincy C. Moore,¹ Megumi Fujioka Mills,¹ Larry S. McDaniel,^1,2,3* and Stephanie Carmicle^1,

Departments of Microbiology,¹ Surgery,² Medicine, University of Mississippi Medical Center, Jackson, Mississippi 39216³

Received 2 April 2007/ Returned for modification 13 May 2007/ Accepted 31 May 2007

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Pneumococcal surface protein C (PspC) binds to both human secretory immunoglobulin A (sIgA) and complement factor H (FH). FH, a regulator of the alternative pathway of complement, can also mediate adherence of different host cells. Since PspC contributes to adherence and invasion of host cells, we hypothesized that the interaction of PspC with FH may also mediate adherence of pneumococci to human cells. In this study, we investigated FH- and sIgA-mediated pneumococcal adherence to human cell lines in vitro. Adherence assays demonstrated that preincubation of Streptococcus pneumoniae D39 with FH increased adherence to human umbilical vein endothelial cells (HUVEC) 5-fold and to lung epithelial cells (SK-MES-1) 18-fold, relative to that of D39 without FH on the surface. The presence of sIgA enhanced adherence to SK-MES-1 6-fold and to pharyngeal epithelial cells (Detroit 562) 14-fold. Furthermore, sIgA had an additive effect on adherence to HUVEC; specifically, preincubation of D39 with both FH and sIgA led to a 21-fold increase in adherence. Finally, using a mouse model, we examined the significance of the FH-PspC interaction in pneumococcal nasal colonization and lung invasion. Mice intranasally infected with D39 preincubated with FH had increased bacteremia and lung invasion, but they had similar levels of nasopharyngeal colonization compared to that of mice challenged with D39 without FH.

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Streptococcus pneumoniae is responsible for diseases ranging from otitis media and sinusitis to more serious manifestations such as pneumonia, septicemia, and meningitis (10, 26, 40). An important characteristic of pneumococci is that the organism can asymptomatically colonize the mucosal surface of the nasopharynx (5, 44). The transition from colonization to invasion involves genotypic and phenotypic changes in protein-dependent and protein-independent mechanisms, many of which lead to enhanced adherence of pneumococci to host cells (18, 21).

Pneumococcal surface protein C family (PspC) proteins (also called CbpA and SpsA [10, 16, 36]) recruit complement factor H (FH) to the pneumococcal surface in vitro and in vivo (9, 10, 19, 32). The binding site for PspC to FH has been mapped to short consensus repeats 6 to 10 of human FH (10). Studies demonstrated that a highly conserved 12-amino-acid motif within the N-terminal 89 amino acids of PspC is required for FH binding and for FH recruitment to viable pneumococci (24). PspC can also bind to human secretory immunoglobulin A (sIgA) (14, 15, 47). The binding site for human secretory component (SC) had been mapped to a conserved hexapeptide motif (YRNYPT) within the -helical domain of PspC (17). The interaction of PspC with SC appears to be limited to human SC and sIgA; specifically, PspC does not bind to rabbit or mouse SC or sIgA (14, 47). Furthermore, PspC can interact with human FH and sIgA concurrently, and these host proteins have distinct binding sites within the -helical domain of PspC (11).

Of the many biological functions that have been characterized for PspC, its role in adherence is one of the functions studied most. While PspC does not exclusively govern pneumococcal adherence, its absence significantly reduces adherence and invasion of human cells (36). Previous studies have demonstrated that pspC is upregulated upon contact with epithelial cells, and its expression is required for translocation to the lower respiratory tract and invasion of cerebrospinal fluid (28, 29). PspC directly participates in pneumococcal adherence by binding to glycoconjugates and sialic acid residues that are abundantly present on host cells (5, 15, 18, 25, 36, 39). The interaction of PspC with the SC of human sIgA and with the SC of the polymeric Ig receptor (pIgR) on mucosal epithelial cells facilitates adherence to and transcytosis of mucosal epithelial cells (14, 15, 47).

FH, a complement regulatory protein of the alternative pathway, is produced by the liver and constitutively expressed by specific endothelial and epithelial cells (12, 30, 37, 42). In addition to its function in complement regulation, FH can act as an adhesion ligand for neutrophils and platelets and may also participate in immune adherence of various host tissues (1, 13, 20). In this study, we have investigated whether FH mediates adherence of pneumococci to human umbilical vein endothelial cells (HUVEC). Since the adherence properties of FH may not be limited to endothelial cells, we have examined the ability of the FH-PspC interaction to tether pneumococci to both pharyngeal (Detroit 562) and lung (SK-MES-1) epithelial cell lines. As PspC also binds human sIgA (10, 16), we have investigated both the FH-PspC and sIgA-PspC interactions in adherence. Using cells from both the upper and lower respiratory tracts, we examined the abilities of the FH-PspC and sIgA-PspC interactions to tether pneumococci to specific human cell lines in vitro. The dual acquisition of host FH and sIgA could contribute to pneumococcal adhesion and invasion. Finally, we demonstrated the significance of the FH-PspC interaction in pneumococcal nasal colonization and lung invasion, using a mouse model. While various adherence mechanisms have been characterized for pneumococci, the specific interaction of PspC with FH represents a novel mechanism that tethers pneumococci to host tissues.

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Bacterial strains and growth conditions. S. pneumoniae strains used in this study were D39, a mouse virulent capsular serotype 2 strain, and TRE108, an isogenic mutant of D39 that lacks PspC and does not bind FH (2, 9). Bacteria were grown to mid-log phase as described previously (32), harvested by centrifugation, and stored in aliquots containing 10% glycerol at –80°C. Erythromycin (0.5 µg/ml) was added to growth medium for TRE108.

Cell culture. Human cell lines used in this study were obtained from ATCC and include a HUVEC line, a pharyngeal epithelial cell line (Detroit 562), and a lung epithelial cell line (SK-MES-1). HUVEC were maintained in Dulbecco's modified Eagle's medium containing 10% heat-inactivated fetal bovine serum (FBS; HyClone). Epithelial cell lines were maintained in minimal essential medium (MEM) plus 1 mM sodium pyruvate (HyClone), 1.5 g/liter sodium bicarbonate (Sigma), and 10% FBS. Cells from passages 1 to 3 were used for all experiments. Cells were transferred to 24-well plates for adherence assays.

Pneumococcal adherence experiments. Pneumococci used for adherence experiments included D39 preincubated with 10 µg of purified FH (a gift from M. K. Pangburn), designated D39-FH, 10 µg of sIgA purified from human colostrum (17) (a gift from S. Hammerschmidt), designated D39-sIgA, or D39 incubated in the presence of equal concentrations of FH and sIgA (D39, FH, and sIgA) for 20 min at 37°C. Inhibition of pneumococcal adherence was tested using 10 µg of goat antiserum against human FH (Quidel) or 10 µg of rabbit antiserum generated against PspC (LXS 234 [7]). Assays were also conducted in the presence of control sera, including normal rabbit serum and normal goat serum (MP Biomedical). The bacterial mixtures were added to monolayers and incubated as described below.

Adherence assays were performed as described previously (3). Briefly, confluent human cell monolayers (approximately 10⁶ cells) were washed twice with phosphate-buffered saline (PBS) and provided serum-free growth medium for 24 h. Pneumococci (diluted to 10⁷ CFU in 1 ml of serum-free MEM) were added to the wells in triplicate. Inoculated plates were centrifuged at 300 x g for 5 min and then incubated at 37°C in 5% CO₂ for 30 min. Unbound pneumococci were removed by washing the wells three times with 1 ml of PBS. Human cells were detached by treatment with 0.025% trypsin-EDTA. The number of adherent bacteria was determined by plating serial dilutions on blood agar plates. Adherence assays were independently repeated at least six times for each condition tested, and results were compared by analysis of variance using InStat (GraphPad Software, Inc.).

Animal experiments. Groups of naïve CBA/CAHN-XID/J (CBA/N) mice (Jackson Laboratories) received intranasal (IN) challenges with D39 or D39-FH at a concentration of 10⁷ CFU pneumococci in a volume of 10 µl of lactated Ringer's solution. The challenge dose was verified by plate count. Initial studies performed using D39 demonstrated that 48 h provided an optimum time point required to stably achieve carriage while at the same time establishing bacteremia and lung invasion. Therefore, at 48 h postinfection, blood was collected from anesthetized mice by retro-orbital bleeding, and following euthanasia, lung tissue and nasal washes were collected as described previously (6). Briefly, lung tissue was harvested and homogenized, and nasal washes were performed by introducing 150 µl of lactated Ringer's solution into the trachea and collecting approximately 100 µl of outflow from the nose of each mouse. Plate counting was performed on blood agar supplemented with 4 µg/ml gentamicin (BD Biosciences) to determine the numbers of pneumococci present in the samples, as described previously (6), and results were compared using Student's t test. P values 0.05 were considered significant. The detection limit of bacteria in blood, nasal washes, and lung homogenates was 50 CFU per mouse.

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FH and sIgA binding increases pneumococcal adherence to HUVEC. Since others have demonstrated reduced adherence of PspC-deficient pneumococcal strains (35, 36), we compared the adherence of strain D39 to that of TRE108 (PspC^–). Briefly, confluent monolayers were washed, pneumococci were added, and the number of adherent bacteria was determined following a 30-min incubation period. As expected, D39 was approximately eightfold more adherent to the human cell lines than TRE108 (P < 0.001; data not shown). Using purified FH, which we have previously shown to bind to PspC (9, 10, 32), we then investigated whether precoating pneumococci with FH enhanced pneumococcal adherence to human cell lines in vitro. The results of adherence assays using HUVEC demonstrated that D39-FH was fivefold more adherent than D39 without FH on the surface (Table 1 and Fig. 1). Also, D39-sIgA had a 10-fold increased adherence to HUVEC. Additionally, we investigated the combined effect of FH and sIgA on pneumococcal adherence. Interestingly, the combination of sIgA and FH had an additive effect on pneumococcal adherence to HUVEC, leading to a 21-fold increase (Table 1 and Fig. 1). Since HUVEC produce FH (30), we used FH antiserum to diminish the interaction of pneumococci with endogenously produced FH. Pneumococcal adherence was decreased approximately fivefold in the presence of FH antiserum, relative to that of D39 in medium alone or in the presence of control normal goat serum. As an additional control, assays were also performed in the presence of PspC antiserum, which should interfere with the interaction of PspC with the cells (35). The presence of the PspC-specific antiserum reduced adherence approximately fivefold relative to that of D39 in medium alone or in the presence of control normal rabbit serum, suggesting that the specific interaction of PspC with FH was likely responsible for enhanced pneumococcal adherence.

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TABLE 1. Adherence of S. pneumoniae D39 to HUVEC, SK-MES-1, and Detroit 562a

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FIG. 1. Adherence of D39 to HUVEC in the presence of FH and sIgA. Adherence assays were conducted using D39 incubated with FH or sIgA or with both prior to exposure to HUVEC. Assays were also performed in the presence of FH- or PspC-specific antiserum. Data represent the (n-fold) change in adherence of the samples relative to the D39 adherence to HUVEC in the presence of cell culture medium alone. *, P < 0.04; and **, P < 0.001, relative to D39 alone.

FH and sIgA binding increases pneumococcal adherence to SK-MES-1. Since PspC expression is required for infection and multiplication in the lungs (28), we investigated whether PspC-recruited FH also enhanced pneumococcal adherence to lung epithelial cells (SK-MES-1) in vitro. Again, D39-FH bacteria were 18-fold more adherent than D39 (Table 1 and Fig. 2). Likewise, sIgA enhanced adherence sixfold. These results suggested the possibility of a more important role for FH, as opposed to sIgA, in pneumococcal adherence to these lung epithelial cells. In contrast to data from adherence to endothelial cells, preincubation of D39 with both FH and sIgA did not additively increase adherence to lung epithelial cells. In these experiments, the presence of FH- or PspC-specific antiserum caused a fourfold reduction in pneumococcal adhesion (Table 1 and Fig. 2).

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FIG. 2. Adherence of D39 to SK-MES-1 in the presence of FH and sIgA. Adherence assays were conducted using D39 incubated with FH or sIgA or with both prior to exposure to SK-MES-1. Assays were also performed in the presence of FH- or PspC-specific antiserum. Data represent the (n-fold) change in adherence of the samples relative to D39 adherence to SK-MES-1 in the presence of cell culture medium alone. *, P < 0.05; and **, P < 0.001, relative to D39 alone.

sIgA binding increases pneumococcal adherence to Detroit 562 cells. PspC expression is increased during nasopharyngeal colonization in mice (2, 31). Increased adherence to host cells could be due to this intrinsic increase in surface expression of PspC in the presence of a specific epithelial cell type. Therefore, we investigated the role of FH in mediating pneumococcal adherence to a pharyngeal epithelial cell line (Detroit 562). The adherence of D39-FH to Detroit 562 was not increased relative to that of D39 (Table 1 and Fig. 3). These results suggested that pneumococcal adherence to Detroit 562 cells attributed to FH binding to PspC may have been partially masked in this cell type. Conversely, D39-sIgA was 14-fold more adherent than the D39 cells that had not been preincubated with sIgA. Furthermore, pneumococcal adherence was not significantly reduced in the presence of either anti-PspC or anti-FH antiserum (Table 1 and Fig. 3).

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FIG. 3. Adherence of D39 to Detroit 562 in the presence of FH and sIgA. Adherence assays were conducted using D39 incubated with FH or sIgA or with both prior to exposure to Detroit 562. Assays were also performed in the presence of FH- or PspC-specific antiserum. Data represent the (n-fold) change in adherence of the samples relative to D39 adherence to Detroit 562 in the presence of cell culture medium alone. *, P < 0.05; and **, P < 0.01, relative to D39 alone.

Pneumococcal nasopharyngeal colonization and lung invasion. To investigate the roles of FH in pneumococcal nasal colonization and lung invasion, we compared colonization and invasion by D39 to those by D39-FH. Forty-eight hours following IN infection, we compared the density of pneumococci in nasal washes, lung homogenates, and blood, and the number of pneumococci is shown in Fig. 4. As expected, by 48 h, we observed a reduction in the number of pneumococci present in nasal washes relative to that of the initial inoculum. Also, although the presence of FH at the time of infection did not increase proliferation of pneumococci maintained in the carriage state, FH did enhance the progression of invasive pneumococcal disease. Mice infected with D39-FH had significantly more pneumococci present in the blood (P = 0.003) and in the lung (P = 0.001) compared to mice infected with D39 alone. Again, there was no significant difference (P = 0.6) between D39 and D39-FH present in nasal washes.

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FIG. 4. Pneumococcal nasopharyngeal colonization, lung invasion, and bacteremia. Groups of four mice received IN challenges with 107 CFU of either D39 alone or D39 that were preincubated with 20 µg of purified FH (D39-FH). At 48 h postinfection, viable pneumococci in blood, nasal washes, and lung homogenates were enumerated by plate counting. Data demonstrate the numbers of pneumococci present within the samples expressed as log CFU/ml ± standard error of the mean of three independent experiments. In a comparison of D39 to D39-FH in blood, lung, and nasal washes, P values were 0.002 (*), 0.02 (**), and 0.4, respectively.

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Colonization of the human nasopharynx is a prerequisite for establishment of pneumococcal disease (5, 44). The pneumococcus is a prototypical extracellular bacterial pathogen and, thus, is susceptible to elimination by phagocytosis and intracellular killing. However, pneumococci utilize mechanisms for cell-specific internalization and dissemination throughout the host (4, 15). Recent studies have indicated that specific surface proteins are not only required for maintenance of the carriage state but also allow invasion of mucosal barriers (6).

The pneumococcus has several mechanisms that permit adherence to epithelial and endothelial cells (14, 18, 34). One strategy involves the utilization of proteoglycans, such as heparin, as a coreceptor for adherence to human cells (41). Recent studies indicate that pneumococci may increase adherence to host cells by the use of pilus-like structures that project from the pneumococcal cell surface (3). Furthermore, pneumococci can undergo spontaneous and reversible phase variation, which is identifiable based on a change in the colony morphology (8). Results from mouse studies indicate that following infection with either phenotype, opaque variants are the primary phenotype found in blood (36, 45). In contrast, transparent variants predominate during natural carriage in humans (22). It is particularly the transparent phenotype that correlates with increased pneumococcal adherence (8). This adherence is thought to be attributed to increased exposure of adhesins, which is a result of reduced capsular polysaccharide production by transparent variants (38) and increased expression of PspC (2).

Choline-binding proteins, such as PspC, are also important in pneumococcal adherence. Adhesion of pneumococci to pharyngeal epithelial cells is abolished following elution of choline-binding proteins, including PspC, from the pneumococcal surface (35). Also, the interaction between PspC and the extracellular domain of the pIgR facilitates transcytosis of human cells (14, 15). In addition to recruiting FH and sIgA, PspC can also recruit free SC (16). Due to the abundance of free SC and sIgA in human mucosal sites, the interaction of PspC with these host molecules may promote adherence and hinder phagocytosis (15). Dave et al. previously demonstrated that human FH and sIgA have distinct binding sites on PspC and that both proteins can simultaneously bind PspC on viable pneumococci (10).

In addition to its function in complement regulation, FH can act as an adhesion ligand for neutrophils and platelets and may also participate in immune adherence of various host tissues (1, 13, 20). Therefore, we used human cell lines, including those from both the upper and lower respiratory tracts, to investigate FH-mediated pneumococcal adherence to tissues in which PspC expression is important for infection (2). We have examined the effects of FH on pneumococcal adherence to human endothelial, pharyngeal epithelial, and lung epithelial cells. While various adherence mechanisms have been characterized for pneumococci, we sought to determine whether the specific interaction of PspC with FH and sIgA represents a novel mechanism for pneumococcal adherence to human tissues.

Pneumococcal adherence was investigated by incubating bacteria, added at a multiplicity of infection of 10:1 (bacteria/cells), with human cell monolayers for 30 min. This brief incubation period provided ample time to allow for bacterial adherence without negatively affecting cell viability. Since others have demonstrated reduced adherence of PspC-deficient pneumococcal strains (35, 36), we first compared the adherence of strain D39 to that of TRE108 (PspC^–). As expected, D39 bacteria were significantly more adherent to the human cell lines than TRE108 (P < 0.001). We then investigated whether precoating pneumococci with exogenous FH enhanced pneumococcal adherence to human cells in vitro. Initially, we used HUVEC to investigate the interaction between pneumococci and endothelial cells. Our results demonstrated that precoating pneumococci with either FH or sIgA increased their adherence to HUVEC. Interestingly, the presence of both FH and sIgA led to an additive increase in pneumococcal adherence. Furthermore, the presence of the PspC- or FH-specific antiserum reduced adherence to HUVEC, suggesting that the PspC-FH interaction was responsible for enhanced pneumococcal adherence. Additional studies are required to fully investigate the mechanisms by which FH and sIgA mediate adherence to this cell type; however, increased pneumococcal adherence caused by the presence of sIgA may be attributed to direct binding of IgA to endothelial cells (46).

Furthermore, we demonstrated that FH binding is more important in pneumococcal adherence to lung epithelial cells (SK-MES-1) than sIgA binding. This minimal effect of sIgA on adherence of pneumococci to this cell type may be due to minimal expression of pIgR by lung epithelial cells of the lower respiratory tract (2). In contrast, the presence of sIgA, unlike FH, did enhance pneumococcal adherence to pharyngeal epithelial cells (Detroit 562). Since PspC expression is upregulated during nasopharyngeal colonization (2, 31), subtle differences in adherence level to Detroit 562 cells may have been masked in this cell type. Also, unlike lung epithelial cells, pIgR is highly expressed in the pharyngeal epithelium of the upper respiratory tract (2). Therefore, pneumococcal adherence to Detroit 562 may be due to the interaction between sIgA-PspC and pIgR present on the epithelial cells, as opposed to an interaction with FH present on the pneumococcal surface. While further investigation is required to fully elucidate whether pneumococcal adherence to human tissues correlates with different levels of pIgR expressed by a particular cell type, support for this hypothesis is observed in the adherence assay results of our study.

Finally, using an IN challenge model, we investigated the role of FH in nasopharyngeal colonization, bacteremia, and lung invasion. At 48 h postinfection, we observed a reduction in pneumococci recovered from nasal washes, blood, and lung homogenates relative to the number in the initial inoculum. This was not unexpected as normal host innate immunity promotes clearance and restricts invasion of the nasal mucosa (6, 43). In this study, FH did not seem to increase the level of noninvasive nasal colonization, although FH present on the pneumococcal surface at the time of infection appeared to promote the development of more severe pneumococcal disease. Our study demonstrated that the binding of FH to PspC functions in the establishment of pneumococcal bacteremia following IN infection. These data are in agreement with our previous study, which demonstrated that FH-bound D39 had increased proliferation in blood following intravenous infection, ultimately leading to a more rapid progression of pneumococcal disease (32). We also demonstrated that FH enhanced the level of lung invasion. While this infection model indicated an important role for FH during pneumococcal bacteremia and pneumonia, we limited our study to the 48-h time point. At this time point, we consistently achieved nasal colonization while concurrently detecting pneumococcal bacteremia and lung invasion. However, time course studies may be needed to reveal further differences in pneumococcal colonization and lung invasion attributed to FH binding.

A limitation of our study is that in vitro adherence conditions do not absolutely mimic an in vivo host environment, as the interaction of pneumococci with host cells is complex and in some cases host specific. Taken together, the adherence assays using human cell lines and the in vivo mouse data suggest that, within specific host tissues, the interaction of PspC with FH may serve more than one function. FH, while preventing detection of the pneumococcus by the complement system (33), may tether pneumococci to specific cell types. Concurrently, the binding of sIgA facilitates adherence (14, 47) and may ultimately lead to increased migration from mucosal sites to distal host environments.

Identification of major mechanisms used by pneumococci to adhere to and invade the mucosa is important to the development of targeted therapeutic interventions against pneumococcal colonization and disease. For example, several studies have demonstrated that antibodies against PspC protect mice against carriage and sepsis (7, 27). Furthermore, antibodies against PspC can be detected in convalescent-phase sera collected from patients with pneumococcal bacteremia (23). Together, these studies underline the medical importance of examining the interactions between PspC and host proteins. Because mucosal pathogens share many phenotypes, these results could help identify bacterial or host factors that have broad significance to virulence mechanisms of pathogens distinct from those examined here.

 
We thank Michael K. Pangburn and Sven Hammerschmidt for providing the purified human FH and sIgA, respectively. We are also grateful to Babbette Lamarca for support with the tissue culture experiments, to Edwin Swiatlo and Pratik Shah for technical assistance, and to Mary Marquart for generating the polyclonal PspC antiserum.

This study was partially supported by an Alliance for Graduate Education in Mississippi (AGEM) award from the National Science Foundation.

 
* Corresponding author. Mailing address: Department of Microbiology, University of Mississippi Medical Center, 2500 North State Street, Jackson, MS 39216. Phone: (601) 984-6880. Fax: (601) 984-1708. E-mail: LMcDaniel{at}microbio.umsmed.edu

Published ahead of print on 11 June 2007.

Editor: A. Camilli

Current address: Department of Microbiology and Immunology, University of North Carolina, Chapel Hill, NC 27599.

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Infection and Immunity, August 2007, p. 4082-4087, Vol. 75, No. 8
0019-9567/07/$08.00+0     doi:10.1128/IAI.00474-07
Copyright © 2007, American Society for Microbiology. All Rights Reserved.

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