Protein A Suppresses Immune Responses during Staphylococcus aureus Bloodstream Infection in Guinea Pigs

Abstract

Staphylococcus aureus infection is not associated with the development of protective immunity, and disease relapses occur frequently. We hypothesize that protein A, a factor that binds immunoglobulin Fcγ and cross-links VH3 clan B cell receptors (IgM), is the staphylococcal determinant for host immune suppression. To test this, vertebrate IgM was examined for protein A cross-linking. High VH3 binding activity occurred with human and guinea immunoglobulin, whereas mouse and rabbit immunoglobulins displayed little and no binding, respectively. Establishing a guinea pig model of S. aureus bloodstream infection, we show that protein A functions as a virulence determinant and suppresses host B cell responses. Immunization with SpAKKAA, which cannot bind immunoglobulin, elicits neutralizing antibodies that enable guinea pigs to develop protective immunity.Importance Staphylococcus aureus is the leading cause of soft tissue and bloodstream infections; however, a vaccine with clinical efficacy is not available. Using mice to model staphylococcal infection, earlier work identified protective antigens; however, corresponding human clinical trials did not reach their endpoints. We show that B cell receptor (IgM) cross-linking by protein A is an important immune evasion strategy of S. aureus that can be monitored in a guinea pig model of bloodstream infection. Further, immunization with nontoxigenic protein A enables infected guinea pigs to elicit antibody responses that are protective against S. aureus. Thus, the guinea pig model may support preclinical development of staphylococcal vaccines.

Metabolites alleviate staphylococcal bloodstream infection in a NO-dependent manner via arginase inhibition

“…Serial dilutions of homogenate were sampled on TSA and incubated for colony formation overnight at 37°C. The remaining organ was investigated by histopathology analysis (51). For survival, S. aureus USA300 or MRSA252 were chosen.…”

Animal and Human Tissue Models of Vertical Listeria monocytogenes Transmission and Implications for Other Pregnancy-Associated Infections

“…Guinea pig tuberculosis models have a low infectious dose and are able to form granulomas (62). Similarly, studies with Legionella pneumophila (63,64) and Staphylococcus aureus (65)(66)(67) have demonstrated close similarities to humans in susceptibility and infection routes. This makes them a good model for preclinical drug and vaccine development for diseases that poorly infect smaller animal models.…”

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).…”