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  • Title: Protein A suppresses immune responses during Staphylococcus aureus bloodstream infection in guinea pigs.
    Author: Kim HK, Falugi F, Thomer L, Missiakas DM, Schneewind O.
    Journal: mBio; 2015 Jan 06; 6(1):. PubMed ID: 25564466.
    Abstract:
    UNLABELLED: 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 V(H)3 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 V(H)3 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 SpA(KKAA), 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.
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