Leptospirosis: a Toll road from B lymphocytes

Abstract

Leptospirosis is a widespread zoonosis caused by Leptospira interrogans, a pathogen transmitted by asymptomatic infected rodents. Leptospiral lipoproteins and lipopolysaccharide (LPS) have been shown to stimulate murine cells via Toll-like receptors (TLRs) 2 and 4. Host defense mechanisms remain obscure, although TLR4 has been associated with clearing Leptospira. In a recent study, we showed that in response to Leptospira infection, double (TLR2 and TLR4) knock-out (DKO) mice unexpectedly developed TLR-independent pro-inflammatory responses, and rapidly died from severe hepatic and renal failure. Subsequent analysis of chimeric and transgenic mice identified B-cells as the crucial lymphocyte subset responsible for the clearance of Leptospira, initially through the production of specific TLR4-dependent immunoglobulin M (IgM), directed against the LPS of Leptospira, and subsequently through specific IgG production, which is impaired in DKO mice. We also identified the protective, tissue-compartmentalized, TLR2/TLR4-mediated production of interferon-γ(IFN-γ) by B- and T-lymphocytes. Overall, our recent findings demonstrate that TLR2 and TLR4 both play a key role in the early control of leptospirosis, and constitute the first line of defense against Leptospira, confirming previous in vitro data showing that both LPS and lipoprotein play a crucial role in cell activation. However, if this first line of defense is by-passed, Leptospira can induce a deleterious inflammation in the target organs, and this does not rely on TLR activation.