Interaction of clinical isolates of<i>Streptococcus pneumoniae</i>with human complement factor H

Quin, Lisa R.; Onwubiko, Chinwendu; Carmicle, Stephanie; McDaniel, Larry S.

doi:10.1111/j.1574-6968.2006.00439.x

Cited by 13 publications

(18 citation statements)

References 26 publications

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“…The improved survival of pneumococci expressing PspC or Hic in a systemic mouse infection model and in microglial cells provides further evidence for the importance and versatility of PspC in different host niches (29,31). A recent study indicated that carriage isolates, which produce lesser amounts of CPS than the invasive isolates, recruit significantly more factor H than the systemic isolates (53). Similarly, our binding experiments indicate that the CPS interferes with the recruitment of factor H.…”

Section: Discussionsupporting

confidence: 47%

The Host Immune Regulator Factor H Interacts via Two Contact Sites with the PspC Protein of Streptococcus pneumoniae and Mediates Adhesion to Host Epithelial Cells

Hammerschmidt

Agarwal

Kunert

et al. 2007

The Journal of Immunology

124

139

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Pneumococcal surface protein C (PspC) of Streptococcus pneumoniae is a key virulence factor that mediates adhesion to host cells and immune evasion of the host complement. PspC binds the host immune and complement regulator factor H, which is composed of 20 short consensus repeats (SCR). This interaction contributes to pneumococcal virulence. In this study, we identified within the factor H protein two separate PspC binding regions, which were localized to SCR8–11 and SCR19–20, by using recombinant factor H deletion constructs for Western blotting assays and surface plasmon resonance studies. A detailed analysis of binding epitopes in these SCR by peptide spot arrays identified several linear binding regions within the sequences of SCR8–11 and SCR19–20. In addition, the factor H binding site was mapped within the pneumococcal PspC protein to a 121-aa-long stretch positioned in the N terminus (residues 38–158). Factor H attached to the surface of pneumococci via PspC significantly enhanced pneumococcal adherence to host epithelial and endothelial cells. This adhesion was specific and was blocked with a truncated N-terminal factor H-binding fragment of PspC. In conclusion, the acquisition of factor H by pneumococci via PspC occurs via two contact sites located in SCR8–11 and SCR19–20, and factor H attached to the surface of the pneumococcus promotes adhesion to both host epithelial and endothelial cells.

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Section: Discussionsupporting

confidence: 47%

The Host Immune Regulator Factor H Interacts via Two Contact Sites with the PspC Protein of Streptococcus pneumoniae and Mediates Adhesion to Host Epithelial Cells

Hammerschmidt

Agarwal

Kunert

et al. 2007

The Journal of Immunology

124

139

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“…For the remaining strain, an ST6A strain, there was a low level of FH binding in serum to the ⌬pspC strain compared to bacteria incubated on PBS although the biological significance of this is uncertain. As has been recently demonstrated for a large number of clinical isolates (36), the degree of FH binding (represented by a fluorescence index) (9,49) varied significantly between the strains (Fig. 1D).…”

Section: Resultsmentioning

confidence: 59%

“…Furthermore, allelic variation of PspC will affect the avidity of antibody to each allelic variant and means that different sets of primers for real-time PCR will be necessary, complicating accurate investigation of PspC expression. Allelic variations in PspC structure (17,36) may also affect FH binding and could be investigated by exchanging pspC alleles between strains. The effects of loss of PspC on C3b/iC3b deposition were strikingly varied, with a massive increase in C3b/iC3b deposition on the ST6A ⌬pspC strain, large increases on the ST4 and ST6B ⌬pspC strains, only a small increase on the D39 ST2 ⌬pspC strain, no consistent effect on the ST17 and ST23F FIG.…”

Section: Discussionmentioning

confidence: 99%

The Effects of PspC on Complement-Mediated Immunity to Streptococcus pneumoniae Vary with Strain Background and Capsular Serotype

et al. 2010

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Streptococcus pneumoniae may evade complement activity by binding of factor H (FH), a negative regulator of the alternative pathway, to the surface protein PspC. However, existing data on the effects of FH binding to PspC on complement activity are conflicting, and there is also considerable allelic variation in PspC structure between S. pneumoniae strains that may influence PspC-dependent effects on complement. We have investigated interactions with complement for several S. pneumoniae strains in which the gene encoding PspC has been deleted. The degree of FH binding varied between strains and was entirely dependent on PspC for seven strains. Data obtained with TIGR4 strains expressing different capsular serotypes suggest that FH binding is affected by capsular serotype. Results of immunoblot analysis for C3 degradation products and iC3b deposition assays suggested that FH bound to PspC retained functional activity, but loss of PspC had strikingly varied effects on C3b/iC3b deposition on S. pneumoniae, with large increases on serotype 4, 6A, 6B, and 9V strains but only small increases or even decreases on serotype 2, 3, 17, and 23F strains. Repeating C3b/iC3b assays with TIGR4 strains expressing different capsular serotypes suggested that differences in the effect of PspC on C3b/iC3b deposition were largely independent of capsular serotype and depend on strain background. However, data obtained from infection in complement-deficient mice demonstrated that differences between strains in the effects of PspC on complement surprisingly did not influence the development of septicemia.

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“…The alternative pathway can amplify the amount of C3 initially deposited on the organism. The alternative pathway is inhibited by factor H, and previous studies have shown that pneumococci can bind to factor H (28,(36)(37)(38). Both carriage and invasive strains bound similar amounts of the alternative pathway inhibitor factor H (data not shown), thus making it unlikely that differences in regulation of the alternative pathway positive feedback loop accounted for differences in C3 binding.…”

Section: Discussionmentioning

confidence: 90%

Role of Complement in Host Defense against Pneumococcal Otitis Media

et al. 2009

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Strategies to limit complement deposition on Streptococcus pneumoniae are established as virulence features for invasive disease, but their role in respiratory tract infection requires further analysis. We evaluated complement C3 protein deposition on discordant S. pneumoniae isolates of the same serotype (6A) and their capacity to cause nasopharyngeal (NP) colonization and experimental otitis media (EOM) in an animal model. We compared C3 binding to five 6A isolates from asymptomatic NP carriers with five 6A strains that caused invasive disease, and we observed less C3 (ϳ10-fold less fluorescence) binding to invasive isolates. We selected two high-level C3-binding carriage and two low-level C3-binding invasive 6A isolates for further study. In the EOM model, 11/12 (92%) ears challenged with a low-level C3-binding 6A strain became infected. Only 2/8 (25%) ears challenged with the discordant high-level C3-binding 6A isolate developed disease (P ‫؍‬ 0.005). Results with the second discordant 6A isolate pair were comparable. Cobra venom factor (CoVF) treatment, which depletes C3 and consumes complement, restored virulence of the high-level C3-binding strain; 8/8 (100%) ears in CoVF-treated animals developed EOM compared to only 25% of ears in naïve animals (P ‫؍‬ 0.007). These studies demonstrate the critical role for complement evasion in pneumococcal EOM. Colonization with carriage isolates that bound high levels of C3 caused EOM in fewer animals compared to low-level C3-binding invasive strains. Thus, limiting C3 deposition on the surface of S. pneumoniae correlates with increased incidence of EOM following NP colonization and barotrauma in the animal model.

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Interaction of clinical isolates ofStreptococcus pneumoniaewith human complement factor H

Cited by 13 publications

References 26 publications

The Host Immune Regulator Factor H Interacts via Two Contact Sites with the PspC Protein of Streptococcus pneumoniae and Mediates Adhesion to Host Epithelial Cells

The Host Immune Regulator Factor H Interacts via Two Contact Sites with the PspC Protein of Streptococcus pneumoniae and Mediates Adhesion to Host Epithelial Cells

The Effects of PspC on Complement-Mediated Immunity to Streptococcus pneumoniae Vary with Strain Background and Capsular Serotype

Role of Complement in Host Defense against Pneumococcal Otitis Media

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