title: Toll-like receptor 4 protects against lethal Leptospira interrogans serovar icterohaemorrhagiae infection and contributes to in vivo control of leptospiral burden.
abstract: The roles of innate immune responses in protection from or pathogenesis of severe leptospirosis remain unclear. We examined the role of Toll-like receptors (TLRs) in mouse infection and macrophage responses to Leptospira. C3H/HeJ mice (TLR4 deficient) and C3H/HeJ-SCID mice, but not C3H/OuJ mice (TLR4 intact), died after intraperitoneal infection with Leptospira interrogans 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 Leptospira 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-/- and TLR2-/- mice exhibited no defect in cytokine responses to Leptospira compared to controls. Macrophages from C3H/HeJ, TLR4-/-, and MyD88-/- mice secreted far-lower levels of cytokines than wild-type macrophages in response to Leptospira. 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.
authors.affiliation: Division of Infectious Diseases, Department of Medicine, University of California San Diego, 9500 Gilman Dr. 0640, La Jolla, CA 92093-0640, USA.
authors.forename: Suganya
authors.initials: S
authors.lastname: Viriyakosol
authors.forename: Michael A
authors.initials: MA
authors.lastname: Matthias
authors.forename: Mark A
authors.initials: MA
authors.lastname: Swancutt
authors.forename: Theo N
authors.initials: TN
authors.lastname: Kirkland
authors.forename: Joseph M
authors.initials: JM
authors.lastname: Vinetz
mesh_terms: D000293:Adolescent; D000818:Animals; D016207:Cytokines / Q000378:metabolism; D005260:Female; D006801:Humans; D041383:Leptospira interrogans serovar icterohaemorrhagiae / Q000235:genetics / Q000302:isolation & purification / Q000472:pathogenicity*; D007922:Leptospirosis / Q000276:immunology* / Q000382:microbiology / Q000401:mortality* / Q000473:pathology; D017737:Macrophages, Peritoneal / Q000276:immunology / Q000378:metabolism; D008297:Male; D051379:Mice; D008809:Mice, Inbred C3H; D008810:Mice, Inbred C57BL; D016513:Mice, SCID; D009928:Organ Specificity; D051197:Toll-Like Receptor 4 / Q000235:genetics / Q000378:metabolism*
chemical_list: D016207:Cytokines; D051197:Toll-Like Receptor 4