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,#,**
* INSERM, U773, Centre de Recherche Biomédicale Bichat-Beaujon (CRB3), BP 416, Paris France; Université Paris 7-Denis Diderot, Site Bichat, Paris, Paris, France;
Centre Hospitalier Universitaire de Poitiers, Unité de Pathologie Ultrastructurale et Expérimentale, Université de Poitiers, Poitiers, France;
Institut National de Recherche Agronomique, U1282, Infectiologie Animale et Santé Publique, Nouzilly, France; Institut Pasteur,
Unité Postulante Biologie des Spirochètes,
¶ Unité de Réponses Précoces aux Parasites et Immunopathologie,
|| Unité Génétique Mycobactérienne,
# G5 Biologie et Génétique de la Paroi Bactérienne; and
** INSERM, Groupe Avenir, Paris, France
Leptospirosis is a widespread zoonosis caused by pathogenic Leptospira interrogans that are transmitted by asymptomatic infected rodents. Leptospiral lipoproteins and LPS have been shown to stimulate murine cells via TLRs 2 and 4. Host defense mechanisms remain obscure, although TLR4 has been shown to be involved in clearing Leptospira. In this study, we show that double (TLR2 and TLR4) knockout (DKO) mice rapidly died from severe hepatic and renal failure following Leptospira inoculation. Strikingly, the severe proinflammatory response detected in the liver and kidney from Leptospira-infected DKO mice appears to be independent of MyD88, the main adaptor of TLRs. Infection of chimeric mice constructed with wild-type and DKO mice, and infection of several lines of transgenic mice devoid of T and/or B lymphocytes, identified B cells as the crucial lymphocyte subset responsible for the clearance of Leptospira, through the early production of specific TLR4-dependent anti-Leptospira IgMs elicited against the leptospiral LPS. We also found a protective tissue compartmentalized TLR2/TLR4-mediated production of IFN-
by B and T lymphocytes, in the liver and kidney, respectively. In contrast, the tissue inflammation observed in Leptospira-infected DKO mice was further characterized to be mostly due to B lymphocytes in the liver and T cells in the kidney. Altogether these findings demonstrate that TLR2 and TLR4 play a key role in the early control of leptospirosis, but do not directly trigger the inflammation induced by pathogenic Leptospira.
The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.
1 This work was supported by Institut Pasteur and INSERM research grants. C.C. was sponsored by the French Ministère de la Défense (PhD grant DGA/MRIS).
2 Address correspondence and reprint requests to Dr. C. Werts, Institut Pasteur, G5 Biologie et Génétique de la Paroi Bactérienne, INSERM Groupe Avenir, 28 Rue du Dr Roux, 75724 Paris Cedex 15, France. E-mail address: cwerts{at}pasteur.fr
3 Abbreviations used in this paper used: DKO, double TLR2 and TLR4 knockout; WT, wild type; BUN, blood urea nitrogen; ASAT, aspartate aminotransferase activity; iNOS, inducible NO synthase.
4 The online version of the article contains supplemental materials.
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