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Among the secreted proteome of<jats:named-content content-type=\"genus-species\">Histoplasma<\/jats:named-content>, culture filtrate protein 4 (Cfp4) is a heavily glycosylated factor produced abundantly and specifically by<jats:named-content content-type=\"genus-species\">Histoplasma<\/jats:named-content>yeast cells, suggesting its role in pathogenesis. We have generated three monoclonal antibodies as tools for characterization and detection of Cfp4 and determined the epitope each recognizes. Through site-directed mutagenesis of Cfp4, we identified three asparagines that function as the principal sites of N-linked glycan modification. To test the function of Cfp4 in<jats:named-content content-type=\"genus-species\">Histoplasma<\/jats:named-content>pathogenesis, we generated Cfp4-deficient strains by insertional mutagenesis and by RNA interference. Cfp4-deficient strains are not attenuated in virulence in human macrophages or during lung infection in a murine model of histoplasmosis. Coinfection of differentially marked Cfp4-producing and Cfp4-deficient strains demonstrates that production of Cfp4 does not confer a fitness advantage to<jats:named-content content-type=\"genus-species\">Histoplasma<\/jats:named-content>yeasts during murine lung infection. Despite no apparent role in acute virulence in mice, secretion of the Cfp4 glycoprotein by yeast cells is consistent across clinical and laboratory isolates of the North American type 1 and type 2 phylogenetic groups as well as a strain from Panama. In addition, human immune sera recognize the<jats:named-content content-type=\"genus-species\">Histoplasma<\/jats:named-content>Cfp4 protein, confirming Cfp4 production during infection of human hosts. These results suggest the potential utility of Cfp4 as a diagnostic exoantigen for histoplasmosis.<\/jats:p>","DOI":"10.1128\/iai.01893-14","type":"journal-article","created":{"date-parts":[[2014,8,12]],"date-time":"2014-08-12T04:05:46Z","timestamp":1407816346000},"page":"4414-4425","update-policy":"https:\/\/doi.org\/10.1128\/asmj-crossmark-policy-page","source":"Crossref","is-referenced-by-count":14,"title":["Glycosylation and Immunoreactivity of the Histoplasma capsulatum Cfp4 Yeast-Phase Exoantigen"],"prefix":"10.1128","volume":"82","author":[{"given":"Eric D.","family":"Holbrook","sequence":"first","affiliation":[{"name":"Department of Microbiology, Department of Microbial Infection and Immunity, Ohio State University, Columbus, Ohio, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Megan M.","family":"Kemski","sequence":"additional","affiliation":[{"name":"Department of Microbiology, Department of Microbial Infection and Immunity, Ohio State University, Columbus, Ohio, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Sarah M.","family":"Richer","sequence":"additional","affiliation":[{"name":"MiraVista Diagnostics, Indianapolis, Indiana, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"L. 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