title: Toll-like receptor 4 signalling through MyD88 is essential to control Salmonella enterica serovar typhimurium infection, but not for the initiation of bacterial clearance.
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-gamma (IFN-gamma), and TRIF(-/-) mice produced markedly enhanced IFN-gamma 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.
authors.affiliation: Department of Veterinary Medicine, University of Cambridge, Cambridge, UK.
authors.forename: Suzanne
authors.initials: S
authors.lastname: Talbot
authors.forename: Sabine
authors.initials: S
authors.lastname: Tötemeyer
authors.forename: Masahiro
authors.initials: M
authors.lastname: Yamamoto
authors.forename: Shizuo
authors.initials: S
authors.lastname: Akira
authors.forename: Katherine
authors.initials: K
authors.lastname: Hughes
authors.forename: David
authors.initials: D
authors.lastname: Gray
authors.forename: Tom
authors.initials: T
authors.lastname: Barr
authors.forename: Pietro
authors.initials: P
authors.lastname: Mastroeni
authors.forename: Duncan J
authors.initials: DJ
authors.lastname: Maskell
authors.forename: Clare E
authors.initials: CE
authors.lastname: Bryant
mesh_terms: D000818:Animals; D002478:Cells, Cultured; D007371:Interferon-gamma / Q000096:biosynthesis; D008099:Liver / Q000382:microbiology; D008262:Macrophage Activation / Q000276:immunology; D008264:Macrophages / Q000276:immunology / Q000382:microbiology; D051379:Mice; D008810:Mice, Inbred C57BL; D053594:Myeloid Differentiation Factor 88 / Q000276:immunology*; D009569:Nitric Oxide / Q000096:biosynthesis; D012480:Salmonella Infections / Q000276:immunology* / Q000382:microbiology; D012486:Salmonella typhimurium / Q000254:growth & development* / Q000302:isolation & purification; D015398:Signal Transduction / Q000276:immunology; D013154:Spleen / Q000382:microbiology; D051197:Toll-Like Receptor 4 / Q000276:immunology*; D014409:Tumor Necrosis Factor-alpha / Q000096:biosynthesis
chemical_list: C507780:Myd88 protein, mouse; D053594:Myeloid Differentiation Factor 88; C493487:Tlr4 protein, mouse; D051197:Toll-Like Receptor 4; D014409:Tumor Necrosis Factor-alpha; D009569:Nitric Oxide; D007371:Interferon-gamma