Identification of the Targets of Cross-Reactive Antibodies Induced byStreptococcus pneumoniaeColonization

Abstract

Much of the efficacy of current pneumococcal conjugate vaccines lies in their ability to decrease carriage of vaccine serotypes in the population. Novel and more-broadly acting vaccines would also need to target carriage in order to be as effective. We have previously shown that model murine carriage of Streptococcus pneumoniae can elicit antibody-dependent immunity and can protect against a virulent heterologous challenge strain. This study set out to identify S. pneumoniae surface antigens that may elicit cross-reactive antibodies following colonization. Western blot analysis using sera from colonized mice identified the previously characterized immunogens pneumococcal surface protein A (PspA), putative proteinase maturation protein A (PpmA), and pneumococcal surface adhesin A (PsaA) as such antigens. Using flow cytometry, PspA was found to be the major target of surface-bound cross-reactive IgG in sera from TIGR4⌬cps-colonized mice, with a modest contribution from PpmA and none from PsaA. In human sera, however, only mutants lacking PpmA were shown to have reduced binding of surface IgG compared to wild-type strains, suggesting that prior exposure to S. pneumoniae in humans may induce PpmA antibodies. We also investigated if cross-reactive antibodies induced by these antigens may be cross-protective against carriage. Despite the immunogenicity of PspA, PpmA, and PsaA, mice were still protected following colonization with mutants lacking these antigens, suggesting they are not necessary for cross-protection induced by carriage. Our findings suggest that a whole-organism approach may be needed to broadly diminish carriage.

Streptococcus pneumoniae Colonization Is Required To Alter the Nasal Microbiota in Cigarette Smoke-Exposed Mice

“…The pneumococcal nasal colonization method was adapted from previous reports (16,20). Similar to nasopharyngeal carriage in humans, nasal colonization with TIGR4 (a serotype 4 clinical isolate) was largely asymptomatic and lasted several weeks (21,22), permitting the study of nasal colonization with minimal IPD and survivor bias (16,23). This observation stands in contrast to our previous study, where cigarette smoke exposure predisposed mice colonized with a more invasive S. pneumoniae strain, P1547, to invasive infections (13).…”

“…pneumoniae preparation. Stocks of S. pneumoniae TIGR4, a serotype 4 clinical isolate (16,23), were streaked onto tryptic soy agar (BD Biosciences, Franklin Lakes, NJ) supplemented with 5% sheep blood (Cedarlane, Burlington, ON, Canada) and 5 g/ml neomycin (Sigma-Aldrich, Oakville, ON, Canada). Stocks of S. pneumoniae P1547, a serotype 6A clinical isolate (13), were streaked onto blood agar containing 10 g/ml neomycin.…”

Protection against Streptococcus pneumoniae serotype 1 acute infection shows a signature of Th17- and IFN-γ-mediated immunity

“…Recently, it has been also demonstrated that IL-17A, produced by Th17 cells, is a key factor in protective immunity against pneumococcal colonization (Lu et al 2008), being essential for the recruitment of macrophages and neutrophils to the nasopharynx ). However, other groups have shown evidences that antibodies and particularly IgA are necessary in protection against pneumococcal colonization (Fukuyama et al 2010;Richards et al 2010;Roche et al 2007; Roche and Weiser 2010). Overall, these data suggest that both antibodies and cellular responses may have an important role in protection against pneumococcal nasopharyngeal colonization (Richards et al 2010).…”

The Role of Bacterial Protein Tyrosine Phosphatases in the Regulation of the Biosynthesis of Secreted Polysaccharides

“…For S. pneumoniae, it has been shown that unencapsulated bacteria linger in the nasopharynx of mice for some time (74). Interestingly, the use of such strains as liveattenuated vaccines has provided significant protection against subsequent infection, both from the same and different capsular serotypes (85). Thus, it is interesting to hypothesize that any drug that inhibits these PTPs could also lead to protection against subsequent infection.…”