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C3H\/HeJ mice (TLR4 deficient) and C3H\/HeJ-SCID mice, but not C3H\/OuJ mice (TLR4 intact), died after intraperitoneal infection with<jats:italic>Leptospira interrogans<\/jats:italic>serovar Icterohaemorrhagiae. Death in both C3H\/HeJ mouse strains was associated with jaundice and pulmonary hemorrhage, similar to the patient from whom the isolate was obtained. In chronic sublethal infection, TLR4-deficient mice harbored more leptospires in liver, lung, and kidney than control mice. Heat-killed<jats:italic>Leptospira<\/jats:italic>stimulated macrophages to secrete proinflammatory cytokines, tumor necrosis factor alpha, interleukin-6, and macrophage inflammatory protein 2 not inhibited by polymyxin B, suggesting that leptospiral lipopolysaccharide (LPS) did not drive these responses. Anti-TLR4 and anti-MD-2 but not anti-CD14 monoclonal antibodies inhibited cytokine production. Peritoneal macrophages from CD14<jats:sup>\u2212\/\u2212<\/jats:sup>and TLR2<jats:sup>\u2212\/\u2212<\/jats:sup>mice exhibited no defect in cytokine responses to<jats:italic>Leptospira<\/jats:italic>compared to controls. Macrophages from C3H\/HeJ, TLR4<jats:sup>\u2212\/\u2212<\/jats:sup>, and MyD88<jats:sup>\u2212\/\u2212<\/jats:sup>mice secreted far-lower levels of cytokines than wild-type macrophages in response to<jats:italic>Leptospira<\/jats:italic>. TLR4 plays a crucial role in protection from acute lethal infection and control of leptospiral burden during sublethal chronic infection. Cytokine responses in macrophages correlated with leptospiral clearance. These TLR4-dependent but CD14\/TLR2-independent responses are likely mediated by a leptospiral ligand(s) other than LPS.<\/jats:p>","DOI":"10.1128\/iai.74.2.887-895.2006","type":"journal-article","created":{"date-parts":[[2006,1,21]],"date-time":"2006-01-21T01:42:38Z","timestamp":1137807758000},"page":"887-895","update-policy":"https:\/\/doi.org\/10.1128\/asmj-crossmark-policy-page","source":"Crossref","is-referenced-by-count":116,"title":["Toll-Like Receptor 4 Protects against Lethal<i>Leptospira interrogans<\/i>Serovar Icterohaemorrhagiae Infection and Contributes to In Vivo Control of Leptospiral Burden"],"prefix":"10.1128","volume":"74","author":[{"given":"Suganya","family":"Viriyakosol","sequence":"first","affiliation":[{"name":"Division of Infectious Diseases, Department of Medicine, University of California, San Diego, 9500 Gilman Drive, La Jolla, California 92093-0640"},{"name":"Veterans Administration San Diego Healthcare System and Department of Pathology, University of California, San Diego, 3350 La Jolla Village Drive, La Jolla, California 92161"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Michael A.","family":"Matthias","sequence":"additional","affiliation":[{"name":"Division of Infectious Diseases, Department of Medicine, University of California, San Diego, 9500 Gilman Drive, La Jolla, California 92093-0640"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mark A.","family":"Swancutt","sequence":"additional","affiliation":[{"name":"Division of Infectious Diseases, Department of Medicine, University of California, San Diego, 9500 Gilman Drive, La Jolla, California 92093-0640"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Theo N.","family":"Kirkland","sequence":"additional","affiliation":[{"name":"Division of Infectious Diseases, Department of Medicine, University of California, San Diego, 9500 Gilman Drive, La Jolla, California 92093-0640"},{"name":"Veterans Administration San Diego Healthcare System and Department of Pathology, University of California, San Diego, 3350 La Jolla Village Drive, La Jolla, California 92161"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Joseph M.","family":"Vinetz","sequence":"additional","affiliation":[{"name":"Division of Infectious Diseases, Department of Medicine, University of California, San Diego, 9500 Gilman Drive, La Jolla, California 92093-0640"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"235","reference":[{"key":"e_1_3_2_2_2","doi-asserted-by":"publisher","DOI":"10.1128\/iai.17.1.67-72.1977"},{"key":"e_1_3_2_3_2","doi-asserted-by":"publisher","DOI":"10.1128\/iai.14.3.703-708.1976"},{"key":"e_1_3_2_4_2","first-page":"REVIEWS3011","volume":"3","year":"2002","unstructured":"Armant, M. 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