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We hypothesize that protein A, a factor that binds immunoglobulin Fc\u03b3 and cross-links V<jats:sub>H<\/jats:sub>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<jats:sub>H<\/jats:sub>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.\u00a0aureus bloodstream infection, we show that protein A functions as a virulence determinant and suppresses host B cell responses. Immunization with SpA<jats:sub>KKAA<\/jats:sub>, which cannot bind immunoglobulin, elicits neutralizing antibodies that enable guinea pigs to develop protective immunity.<\/jats:p><jats:p><jats:bold>IMPORTANCE<\/jats:bold>\u2002<jats:named-content content-type=\"genus-species\">Staphylococcus aureus<\/jats:named-content>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.\u00a0aureus 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.\u00a0aureus. Thus, the guinea pig model may support preclinical development of staphylococcal vaccines.<\/jats:p>","DOI":"10.1128\/mbio.02369-14","type":"journal-article","created":{"date-parts":[[2015,1,7]],"date-time":"2015-01-07T03:55:50Z","timestamp":1420602950000},"update-policy":"https:\/\/doi.org\/10.1128\/asmj-crossmark-policy-page","source":"Crossref","is-referenced-by-count":38,"title":["Protein A Suppresses Immune Responses during Staphylococcus aureus Bloodstream Infection in Guinea Pigs"],"prefix":"10.1128","volume":"6","author":[{"given":"Hwan Keun","family":"Kim","sequence":"first","affiliation":[{"name":"Department of Microbiology, University of Chicago, Chicago, Illinois, USA"},{"name":"Howard Taylor Ricketts Laboratory, Argonne National Laboratory, Argonne, Illinois, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Fabiana","family":"Falugi","sequence":"additional","affiliation":[{"name":"Department of Microbiology, University of Chicago, Chicago, Illinois, USA"},{"name":"Howard Taylor Ricketts Laboratory, Argonne National Laboratory, Argonne, Illinois, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lena","family":"Thomer","sequence":"additional","affiliation":[{"name":"Department of Microbiology, University of Chicago, Chicago, Illinois, USA"},{"name":"Howard Taylor Ricketts Laboratory, Argonne National Laboratory, Argonne, Illinois, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Dominique M.","family":"Missiakas","sequence":"additional","affiliation":[{"name":"Department of Microbiology, University of Chicago, Chicago, Illinois, USA"},{"name":"Howard Taylor Ricketts Laboratory, Argonne National Laboratory, Argonne, Illinois, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Olaf","family":"Schneewind","sequence":"additional","affiliation":[{"name":"Department of Microbiology, University of Chicago, Chicago, Illinois, USA"},{"name":"Howard Taylor Ricketts Laboratory, Argonne National Laboratory, Argonne, Illinois, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"235","reference":[{"key":"e_1_3_3_2_2","doi-asserted-by":"publisher","DOI":"10.1056\/NEJM199808203390806"},{"key":"e_1_3_3_3_2","doi-asserted-by":"publisher","DOI":"10.1186\/1471-2334-13-252"},{"key":"e_1_3_3_4_2","doi-asserted-by":"publisher","DOI":"10.1097\/INF.0b013e3182a5c30d"},{"key":"e_1_3_3_5_2","doi-asserted-by":"publisher","DOI":"10.1086\/591698"},{"key":"e_1_3_3_6_2","doi-asserted-by":"publisher","DOI":"10.1128\/CMR.00081-09"},{"key":"e_1_3_3_7_2","doi-asserted-by":"publisher","DOI":"10.1016\/S0140-6736(09)61999-1"},{"key":"e_1_3_3_8_2","doi-asserted-by":"publisher","DOI":"10.1007\/s00281-011-0293-5"},{"key":"e_1_3_3_9_2","doi-asserted-by":"publisher","DOI":"10.1084\/jem.12.1.67"},{"key":"e_1_3_3_10_2","doi-asserted-by":"publisher","DOI":"10.1136\/bmj.2.5350.149"},{"key":"e_1_3_3_11_2","doi-asserted-by":"publisher","DOI":"10.1111\/j.1749-6632.1965.tb11644.x"},{"key":"e_1_3_3_12_2","doi-asserted-by":"publisher","DOI":"10.1111\/j.1365-2958.1994.tb00304.x"},{"key":"e_1_3_3_13_2","doi-asserted-by":"publisher","DOI":"10.1128\/AAC.00096-06"},{"key":"e_1_3_3_14_2","doi-asserted-by":"publisher","DOI":"10.1093\/infdis\/jir141"},{"key":"e_1_3_3_15_2","doi-asserted-by":"publisher","DOI":"10.1128\/iai.64.5.1659-1665.1996"},{"key":"e_1_3_3_16_2","doi-asserted-by":"publisher","DOI":"10.1056\/NEJMoa011297"},{"key":"e_1_3_3_17_2","doi-asserted-by":"publisher","DOI":"10.1126\/science.1081147"},{"key":"e_1_3_3_18_2","doi-asserted-by":"publisher","DOI":"10.1001\/jama.2013.3010"},{"key":"e_1_3_3_19_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.mib.2011.10.012"},{"key":"e_1_3_3_20_2","first-page":"173","article-title":"Effect of protein A of Staphylococcus aureus on the binding of monomeric and polymeric IgG to Fc receptor-bearing cells","volume":"38","author":"Sulica A","year":"1979","unstructured":"Sulica A, Medesan C, Laky M, Onic\u0103 D, Sj\u00f6quist J, Ghetie V. 1979. 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