Peptidoglycan-linked protein A promotes T cell-dependent antibody expansion duringStaphylococcus aureusinfection

Abstract

A hallmark of Staphylococcus aureus disease in humans is persistent infections without development of protective immune responses. Infected patients generate V H 3 plasmablast expansions and increased V H 3 idiotype Ig; however, the mechanisms for staphylococcal modification of immune responses are not known. We report here that S. aureus-infected mice generate V H 3 antibody expansions via a mechanism requiring MHC-restricted antigen presentation to CD4 + T cells and staphylococcal protein A (SpA), a cell wall-anchored surface molecule that binds Fcγ and V H 3 variant heavy chains of Ig. V H 3 expansion occurred with peptidoglycan-linked SpA from the bacterial envelope but not with recombinant SpA, and optimally required five tandem repeats of its Ig-binding domains. Signaling via receptor-interacting serine/threonine protein kinase 2 (RIPK2) was essential for implementing peptidoglycan-linked SpA superantigen activity. V H 3 clan IgG from S. aureus-infected or SpA-treated animals was not pathogen-specific, suggesting that SpA cross-linking of V H 3 idiotype B-cell receptors and activation via attached peptidoglycan are the determinants of staphylococcal escape from adaptive immune responses.

Staphylococcal Protein A Contributes to Persistent Colonization of Mice with Staphylococcus aureus

“…In a mouse model of intravenous S. aureus challenge, released SpA activated B cell proliferation and enhanced secretion of V H 3 idiotype IgM and IgG molecules (33). However, expanded V H 3 idiotype IgG does not recognize staphylococcal antigens (33). The molecular basis Cohorts of C57BL/6J mice were inoculated intranasally with 10 8 CFU of the indicated S. aureus strains.…”

“…In contrast to many toxin and capsular polysaccharide genes and several other surface protein genes, S. aureus expresses spa during colonization of both humans and cotton rats (30,31). Although the tandem-repeat structure of the spa gene promotes high-frequency recombination, human colonization selects for spa alleles whose products maintain five immunoglobulin binding domains (IgBDs), which endows staphylococci with potent B cell superantigen activity (32,33). When analyzed in human volunteers who had been cleared of nasal carriage via mupirocin treatment, S. aureus spa expression was not required for bacterial adherence to human nasal tissue and for initial colonization, i.e., for a 10-day period following inoculation (34).…”

Staphylococcus aureus: Overview of Bacteriology, Clinical Diseases, Epidemiology, Antibiotic Resistance and Therapeutic Approach

“…Virulence factors help in attachment to host cells, breaking down the host immune shield, tissue invasion, causing sepsis and elicit toxin-mediated syndromes. This is the basis for persistent staphylococcal infections without strong host immune response [11]. Based on their mechanism of action and role in pathogenesis, staphylococcal virulence factors are classified as represented in Table 1 [9,12].…”

Targeting fundamental pathways to disrupt Staphylococcus aureus survival: clinical implications of recent discoveries

“…SpA binding to B cell receptors on peripheral murine B cells induces substantial B cell apoptosis in vivo (34), and this apoptotic B cell targeting by SpA is potent and dose dependent (35). In both murine and guinea pig models, WT SpA suppresses B cell responses and leads to clonal apoptosis and prevention of memory responses, both of which are restored during infection with SpA mutant strains (36)(37)(38). Finally, SpA is superantigenic, and apparently human B cells are biased toward SpA at the expense of other important antigens, severely limiting host response (39).…”