title: 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 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.
  
  
  OBJECTIVE
  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.
authors.forename: Hwan Keun
authors.initials: HK
authors.lastname: Kim
authors.forename: Fabiana
authors.initials: F
authors.lastname: Falugi
authors.forename: Lena
authors.initials: L
authors.lastname: Thomer
authors.forename: Dominique M
authors.initials: DM
authors.lastname: Missiakas
authors.affiliation: oschnee@bsd.uchicago.edu.
authors.forename: Olaf
authors.initials: O
authors.lastname: Schneewind
mesh_terms: D000818:Animals; D000907:Antibodies, Bacterial / Q000737:chemistry / Q000276:immunology; D000917:Antibody Formation; D016470:Bacteremia / Q000276:immunology* / Q000382:microbiology; D005260:Female; D006168:Guinea Pigs; D006801:Humans; D057131:Immune Evasion; D007075:Immunoglobulin M / Q000737:chemistry / Q000276:immunology; D051379:Mice; D008807:Mice, Inbred BALB C; D011817:Rabbits; D013203:Staphylococcal Infections / Q000276:immunology* / Q000382:microbiology; D013205:Staphylococcal Protein A / Q000235:genetics / Q000276:immunology*; D013211:Staphylococcus aureus / Q000235:genetics / Q000276:immunology*
chemical_list: D000907:Antibodies, Bacterial; D007075:Immunoglobulin M; D013205:Staphylococcal Protein A