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Toll‐like receptor 4 signalling through MyD88 is essential to control Salmonella enterica serovar Typhimurium infection, but not for the initiation of bacterial clearance
Author(s) -
Talbot Suzanne,
Tötemeyer Sabine,
Yamamoto Masahiro,
Akira Shizuo,
Hughes Katherine,
Gray David,
Barr Tom,
Mastroeni Pietro,
Maskell Duncan J.,
Bryant Clare E.
Publication year - 2009
Publication title -
immunology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.297
H-Index - 133
eISSN - 1365-2567
pISSN - 0019-2805
DOI - 10.1111/j.1365-2567.2009.03146.x
Subject(s) - salmonella enterica , salmonella , microbiology and biotechnology , toll , serotype , toll like receptor , biology , receptor , signalling , salmonella infection , innate immune system , bacteria , immunology , biochemistry , genetics
Summary Toll‐like receptor‐4 (TLR4) is important in protection against lethal Salmonella enterica serovar Typhimurium ( S . Typhimurium) infection. Control of the early stages of sublethal S . Typhimurium infection in mice depends on TLR4‐dependent activation of macrophages and natural killer (NK) cells to drive an inflammatory response. TLR4 signals through the adapter proteins Mal/MyD88 and TRIF‐related adaptor molecule (TRAM)/TIR‐domain‐containing adaptor‐inducing interferon‐b (TRIF). In the mouse typhoid model we showed that TLR4 and MyD88, but not Mal or TRIF, are essential for the control of exponential S . Typhimurium growth. TRIF −/− mice have a higher bacterial load in comparison with wild‐type mice during a sublethal infection because TRIF is important for bacterial killing during the first day of systemic disease. Minimal pro‐inflammatory responses were induced by S . Typhimurium infection of macrophages from TLR4 −/− , MyD88 −/− and TRIF −/− mice in vitro . Pro‐inflammatory responses from Mal −/− macrophages were similar to those from wild‐type cells. The pro‐inflammatory responses of TRIF −/− macrophages were partially restored by the addition of interferon‐γ (IFN‐γ), and TRIF −/− mice produced markedly enhanced IFN‐γ levels, in comparison to wild‐type mice, probably explaining why bacterial growth can be controlled in these mice. TLR4 −/− , MyD88 −/− , TRIF −/− and Mal −/− mice all initiated clearance of S . Typhimurium, suggesting that TLR4 signalling is not important in driving bacterial clearance in comparison to its critical role in controlling early bacterial growth in mouse typhoid.