Toll-like receptor 4 signalling through MyD88 is essential to controlSalmonella entericaserovar Typhimurium infection, but not for the initiation of bacterial clearance

Talbot, S., Totemeyer, S., Yamamoto, M., Akira, S., Hughes, K., Gray, D., Barr, T., Mastroeni, P., Maskell, D.J. and Bryant, C.E. (2009) Toll-like receptor 4 signalling through MyD88 is essential to controlSalmonella entericaserovar Typhimurium infection, but not for the initiation of bacterial clearance. Immunology, 128(4), pp. 472-483. (doi:10.1111/j.1365-2567.2009.03146.x)

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Abstract

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.

Item Type:Articles
Status:Published
Refereed:Yes
Glasgow Author(s) Enlighten ID:Barr, Dr Tom
Authors: Talbot, S., Totemeyer, S., Yamamoto, M., Akira, S., Hughes, K., Gray, D., Barr, T., Mastroeni, P., Maskell, D.J., and Bryant, C.E.
College/School:College of Medical Veterinary and Life Sciences > Institute of Infection Immunity and Inflammation
Journal Name:Immunology
Publisher:Blackwell
ISSN:0019-2805

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