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The mechanisms of disease manifestation in the host remain elusive, and the roles of leptospiral exoproteins in these processes have yet to be determined. Our aim in this study was to assess the composition and quantity of exoproteins of pathogenic<jats:named-content content-type=\"genus-species\">Leptospira interrogans<\/jats:named-content>and to construe how these proteins contribute to disease pathogenesis. Label-free quantitative mass spectrometry of proteins obtained from<jats:named-content content-type=\"genus-species\">Leptospira<\/jats:named-content>spirochetes cultured<jats:italic>in vitro<\/jats:italic>under conditions mimicking infection identified 325 exoproteins. The majority of these proteins are conserved in the nonpathogenic species<jats:named-content content-type=\"genus-species\">Leptospira biflexa<\/jats:named-content>, and proteins involved in metabolism and energy-generating functions were overrepresented and displayed the highest relative abundance in culture supernatants. Conversely, proteins of unknown function, which represent the majority of pathogen-specific proteins (presumably involved in virulence mechanisms), were underrepresented. Characterization of various<jats:named-content content-type=\"genus-species\">L. interrogans<\/jats:named-content>exoprotein mutants in the animal infection model revealed host mortality rates similar to those of hosts infected with wild-type<jats:named-content content-type=\"genus-species\">L. interrogans<\/jats:named-content>. Collectively, these results indicate that pathogenic<jats:named-content content-type=\"genus-species\">Leptospira<\/jats:named-content>exoproteins primarily function in heterotrophic processes (the processes by which organisms utilize organic substances as nutrient sources) to maintain the saprophytic lifestyle rather than the virulence of the bacteria. The underrepresentation of proteins homologous to known virulence factors, such as toxins and effectors in the exoproteome, also suggests that disease manifesting from<jats:named-content content-type=\"genus-species\">Leptospira<\/jats:named-content>infection is likely caused by a combination of the primary and potentially moonlight functioning of exoproteins.<\/jats:p>","DOI":"10.1128\/iai.00427-15","type":"journal-article","created":{"date-parts":[[2015,5,19]],"date-time":"2015-05-19T02:11:13Z","timestamp":1432001473000},"page":"3061-3073","update-policy":"https:\/\/doi.org\/10.1128\/asmj-crossmark-policy-page","source":"Crossref","is-referenced-by-count":40,"title":["Pathogenic Leptospira interrogans Exoproteins Are Primarily Involved in Heterotrophic Processes"],"prefix":"10.1128","volume":"83","author":[{"given":"Azad","family":"Eshghi","sequence":"first","affiliation":[{"name":"Institut Pasteur, Biology of Spirochetes Unit, Paris, France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Elisa","family":"Pappalardo","sequence":"additional","affiliation":[{"name":"University of Oxford, Sir William Dunn School of Pathology, Oxford, United Kingdom"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Svenja","family":"Hester","sequence":"additional","affiliation":[{"name":"University of Oxford, Sir William Dunn School of Pathology, Oxford, United Kingdom"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Benjamin","family":"Thomas","sequence":"additional","affiliation":[{"name":"University of Oxford, Sir William Dunn School of Pathology, Oxford, United Kingdom"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Gabriela","family":"Pretre","sequence":"additional","affiliation":[{"name":"Institut Pasteur, Biology of Spirochetes Unit, Paris, France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mathieu","family":"Picardeau","sequence":"additional","affiliation":[{"name":"Institut Pasteur, Biology of Spirochetes Unit, Paris, France"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"235","reference":[{"key":"e_1_3_3_2_2","doi-asserted-by":"publisher","DOI":"10.1038\/nrmicro2208"},{"key":"e_1_3_3_3_2","first-page":"66","volume-title":"Global morbidity and mortality of leptospirosis: a systematic review","author":"Hagen JE","year":"2013","unstructured":"Hagen JE, Costa F, Kane M, Calcagno J, Ko AI. 2013. 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