Toll-Like Receptor 4 Protects against LethalLeptospira interrogansSerovar 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.

Attenuated Nephritis in Inducible Nitric Oxide Synthase Knockout C57BL/6 Mice and Pulmonary Hemorrhage in CB17 SCID and Recombination Activating Gene 1 Knockout C57BL/6 Mice Infected with Leptospira interrogans

“…This result is in accordance with the hypothesis that the expression of proinflammatory markers by renal tubular cells in vitro after exposure to leptospiral products may be related to the development of interstitial nephritis in vivo (20)(21)(22). The present study confirms previous reports, using mice of other backgrounds (C3H and C3H/HeJ), that immunodeficiency results in high susceptibility to acute infection, rapidly progressing to death (14,19). In addition, immunodeficiency resulted in high loads of leptospires in the target organs, as seen upon necropsy, in accordance with a previous report on C3H/SCID mice (14).…”

“…Rats are the prototype model of resistance to acute lethal infection (3), but consistent with the observation from SCID mice, rats treated with cyclophosphamide (which suppresses humoral immunity) develop PH (18). However, the observation of PH in SCID mice is not reliable because it was observed in the C3H/HeJ mouse strain background (19) but not the C3H background (14). In this study, we reproduced these experiments in the following murine models: CB17 SCID and C57BL/6 recombination activating gene 1 (Rag1) KO mice.…”

“…However, the involvement of auto-antibodies in PH was countered by a description of lethal PH in experimentally infected severe combined immunodeficiency (SCID) mice lacking functional B-and T-lymphocyte subsets (19). Rats are the prototype model of resistance to acute lethal infection (3), but consistent with the observation from SCID mice, rats treated with cyclophosphamide (which suppresses humoral immunity) develop PH (18).…”

Insuficiência renal aguda associada à leptospirose

“…14 In a recent study, 58 patients with leptospirosis and AKI had hemorrhagic diathesis (80%), liver failure (72%), respiratory failure (38%), circulatory failure (33%), pancreatitis (25%), and rhabdomyolysis (5%). 15 Arterial hypotension is common. 16,17 The hemodynamic status and alterations in most patients with severe leptospirosis are similar to those observed in patients with sepsis.…”

Importância do componente C5 do sistema complemento para o controle de leptospirose in vivo em modelos murinos.

“…Camundongos normalmente resistentes à Leptospira podem se tornar susceptíveis se tratados com ciclofosfamida, uma substância imunossupressora que inibe a atividade de linfócitos B e impede a produção de anticorpos, afetando consequentemente a imunidade humoral (Adler, Faine, 1976; . Contudo, mesmo linhagens de camundongos naturalmente susceptíveis a leptospiras podem não apresentar lesões pulmonares quando infectadas com doses consideradas letais para hamsters, sendo necessário aplicar inóculos com grandes quantidades de leptospiras para induzir danos nesse órgão (Marinho et al, 2009;Nally et al, 2005;Viriyakosol et al, 2006). Entre os danos observados no tecido hepático, há desestruturação do padrão de organização das células, pontos de necrose, infiltrados celulares e aumento do número de células de Küppfer.…”