TLR4- and TLR2-mediated B cell responses control the clearance of the bacterial pathogen, Leptospira interrogans.
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-gamma 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.
Chassin
Cécilia
C
INSERM, U773, Centre de Recherche Biomédicale Bichat-Beaujon, BP 416 Paris France.
Picardeau
Mathieu
M
Goujon
Jean-Michel
JM
Bourhy
Pascale
P
Quellard
Nathalie
N
Darche
Sylvie
S
Badell
Edgar
E
d'Andon
Martine Fanton
MF
Winter
Nathalie
N
Lacroix-Lamandé
Sonia
S
Buzoni-Gatel
Dominique
D
Vandewalle
Alain
A
Werts
Catherine
C
D000818:Animals; D016175:B-Lymphocyte Subsets / Q000276:immunology* / Q000382:microbiology* / Q000473:pathology; D005260:Female; D020022:Genetic Predisposition to Disease; D018836:Inflammation Mediators / Q000378:metabolism / Q000502:physiology; D007921:Leptospira interrogans / Q000254:growth & development* / Q000276:immunology; D007922:Leptospirosis / Q000276:immunology* / Q000382:microbiology* / Q000473:pathology; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008822:Mice, Transgenic; D015398:Signal Transduction / Q000235:genetics / Q000276:immunology; D051195:Toll-Like Receptor 2 / Q000172:deficiency / Q000235:genetics / Q000502:physiology*; D051197:Toll-Like Receptor 4 / Q000172:deficiency / Q000235:genetics / Q000502:physiology*
D018836:Inflammation Mediators; C493486:Tlr2 protein, mouse; C493487:Tlr4 protein, mouse; D051195:Toll-Like Receptor 2; D051197:Toll-Like Receptor 4