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A definitive role of the<jats:italic>ctu<\/jats:italic>gene in virulence and pathogenesis of<jats:italic>F. tularensis<\/jats:italic>Schu S4 has not been assessed; thus, an understanding of the significance of this phenotype is long overdue. CTU is a carbon-nitrogen hydrolase encoded by the citrulline ureidase (<jats:italic>ctu<\/jats:italic>) gene (FTT0435) on the<jats:italic>F. tularensis<\/jats:italic>Schu S4 genome. In the present study, we evaluated the contribution of the<jats:italic>ctu<\/jats:italic>gene in the virulence of category A agent<jats:italic>F. tularensis<\/jats:italic>Schu S4 by generating a nonpolar deletion mutant, the \u0394<jats:italic>ctu<\/jats:italic>mutant. The deletion of the<jats:italic>ctu<\/jats:italic>gene resulted in loss of CTU activity, which was restored by transcomplementing the<jats:italic>ctu<\/jats:italic>gene. The \u0394<jats:italic>ctu<\/jats:italic>mutant did not exhibit any growth defect under acellular growth conditions; however, it was impaired for intramacrophage growth in resting as well as gamma interferon-stimulated macrophages. The \u0394<jats:italic>ctu<\/jats:italic>mutant was further tested for its virulence attributes in a mouse model of respiratory tularemia. Mice infected intranasally with the \u0394<jats:italic>ctu<\/jats:italic>mutant showed significantly reduced bacterial burden in the lungs, liver, and spleen compared to wild-type (WT) Schu S4-infected mice. The reduced bacterial burden in mice infected with the \u0394<jats:italic>ctu<\/jats:italic>mutant was also associated with significantly lower histopathological scores in the lungs. Mice infected with the \u0394<jats:italic>ctu<\/jats:italic>mutant succumbed to infection, but they survived longer and showed significantly extended median time to death compared to that shown by WT Schu S4-infected mice. To conclude, this study demonstrates that<jats:italic>ctu<\/jats:italic>contributes to intracellular survival, in vivo growth, and pathogenesis. However,<jats:italic>ctu<\/jats:italic>is not an absolute requirement for the virulence of<jats:italic>F. tularensis<\/jats:italic>Schu S4 in mice.<\/jats:p>","DOI":"10.1128\/jb.00212-09","type":"journal-article","created":{"date-parts":[[2009,6,6]],"date-time":"2009-06-06T01:36:24Z","timestamp":1244252184000},"page":"4798-4806","update-policy":"https:\/\/doi.org\/10.1128\/asmj-crossmark-policy-page","source":"Crossref","is-referenced-by-count":21,"title":["Contribution of Citrulline Ureidase to<i>Francisella tularensis<\/i>Strain Schu S4 Pathogenesis"],"prefix":"10.1128","volume":"191","author":[{"given":"Manish","family":"Mahawar","sequence":"first","affiliation":[{"name":"Center for Immunology and Microbial Disease, Albany Medical College, Albany, New York 12208"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Girish S.","family":"Kirimanjeswara","sequence":"additional","affiliation":[{"name":"Center for Immunology and Microbial Disease, Albany Medical College, Albany, New York 12208"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Dennis W.","family":"Metzger","sequence":"additional","affiliation":[{"name":"Center for Immunology and Microbial Disease, Albany Medical College, Albany, New York 12208"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Chandra Shekhar","family":"Bakshi","sequence":"additional","affiliation":[{"name":"Center for Immunology and Microbial Disease, Albany Medical College, Albany, New York 12208"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"235","reference":[{"key":"e_1_3_2_2_2","doi-asserted-by":"crossref","first-page":"5276","DOI":"10.1016\/j.vaccine.2008.07.051","volume":"26","year":"2008","unstructured":"Bakshi, C. 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