Abstract
ABSTRACTStaphylococcus aureus is a Gram-positive opportunistic pathogen that causes superficial and invasive infections in the hospital and community. High mortality from infection emphasizes the need for improved methods for prevention and treatment. Although S. aureus possesses an arsenal of virulence factors that contribute to evasion of host defenses, few studies have examined long-term humoral and B-cell responses. Adults with acute-phase skin and soft tissue infections were recruited; blood samples were obtained; and S. aureus isolates, including methicillin-resistant strains, were subjected to genomic sequence analysis. In comparisons of acute-phase sera with convalescent-phase sera, a minority (37.5%) of patients displayed 2-fold or greater increases in antibody titers against three or more S. aureus antigens, whereas nearly half exhibited no changes, despite the presence of toxin genes in most infecting strains. Moreover, enhanced antibody responses waned over time, which could reflect a defect in B-cell memory or long-lived plasma cells. However, memory B cells reactive with a range of S. aureus antigens were prevalent at both acute-phase and convalescent-phase time points. While some memory B cells exhibited toxin-specific binding, those cross-reactive with structurally related leucocidin subunits were dominant across patients, suggesting the targeting of conserved epitopes. Memory B-cell reactivity correlated with serum antibody levels for selected S. aureus exotoxins, suggesting a relationship between the cellular and humoral compartments. Overall, although there was no global defect in the representation of anti-S. aureus memory B cells, there was evidence of restrictions in the range of epitopes recognized, which may suggest potential therapeutic approaches for augmenting host defenses.
Highlights
Staphylococcus aureus is a Gram-positive opportunistic pathogen that causes superficial and invasive infections in the hospital and community
Of the 54 S. aureus-infected patients, 59.3% had MRSA infections and 40.7% had methicillinresistant S. aureus (MSSA) infections (Table S2), which are comparable to the results seen in earlier studies demonstrating a high frequency of community-acquired MRSA (CA-MRSA) among soft tissue infection (SSTI) patients
Our investigations demonstrated that adults with S. aureus SSTI have expanded pools of circulating quiescent memory B cells that, upon in vitro reactivation, produce a plethora of antibodies that react with diverse S. aureus exotoxins, including especially high levels of reactivity with leucocidins (Fig. 3; see Fig. S4 in the supplemental material), with greater heterogeneity of reactivity for other virulence factors included in our surveys (Fig. S5)
Summary
Staphylococcus aureus is a Gram-positive opportunistic pathogen that causes superficial and invasive infections in the hospital and community. Whereas circulating memory B cells against S. aureus secreted exotoxins were prevalent, they were dominated by cross-reactivity with structurally related leucocidin subunits, consistent with recognition of conserved epitopes. These findings provide the first evidence of a relationship between the reactivity of antistaphylococcal circulating memory B cells and serum antibody levels. Infection was not associated with a global defect in B-cell memory for S. aureus secreted factors, and responses were highly dominated by cross-reactivity to structurally related exotoxins, which arguably may alone be suboptimal in providing host defenses. The immunobiology of plasma cells, which maintain humoral protection, is largely intertwined with the development of memory B-cell recall responses [18]
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