title: Multiple redundant stress resistance mechanisms are induced in Salmonella enterica serovar Typhimurium in response to alteration of the intracellular environment via TLR4 signalling.
abstract: Toll-like receptor 4 (TLR4) senses bacterial LPS and is required for the control of systemic Salmonella enterica serovar Typhimurium infection in mice. The mechanisms of TLR4 activation and its downstream signalling cascades are well described, yet the direct effects on the pathogen of signalling via this receptor remain unknown. To investigate this we used microarray-based transcriptome profiling of intracellular S. Typhimurium during infection of primary bone marrow-derived macrophages from wild-type and TLR4-deficient mice. We identified 17 S. Typhimurium genes that were upregulated in the presence of functional TLR4. Nine of these genes have putative functions in oxidative stress resistance. We therefore examined S. Typhimurium gene expression during infection of NADPH oxidase-deficient macrophages, which lack normal oxidative killing mechanisms. We identified significant overlap between the 'TLR4-responsive' and 'NADPH oxidase-responsive' genes. This is new evidence for a link between TLR4 signalling and NADPH oxidase activity. Interestingly, with the exception of a dps mutant, S. Typhimurium strains lacking individual TLR4- and/or oxidative stress-responsive genes were not attenuated during intravenous murine infections. Our study shows that TLR4 activity, either directly or indirectly, induces the expression of multiple stress resistance genes during the intracellular life of S. Typhimurium.
authors: Department of Veterinary Medicine, University of Cambridge, Madingley Road, Cambridge CB3 0ES, UK.
authors: John A
authors: JA
authors: Wright
authors: Department of Veterinary Medicine, University of Cambridge, Madingley Road, Cambridge CB3 0ES, UK.
authors: Sabine S
authors: SS
authors: Tötemeyer
authors: Molecular Microbiology Group, Institute of Food Research, Norwich NR4 7UA, UK.
authors: Isabelle
authors: I
authors: Hautefort
authors: Molecular Microbiology Group, Institute of Food Research, Norwich NR4 7UA, UK.
authors: Corinne
authors: C
authors: Appia-Ayme
authors: Molecular Microbiology Group, Institute of Food Research, Norwich NR4 7UA, UK.
authors: Mark
authors: M
authors: Alston
authors: Molecular Microbiology Group, Institute of Food Research, Norwich NR4 7UA, UK.
authors: Vittoria
authors: V
authors: Danino
authors: Department of Veterinary Medicine, University of Cambridge, Madingley Road, Cambridge CB3 0ES, UK.
authors: Gavin K
authors: GK
authors: Paterson
authors: Department of Veterinary Medicine, University of Cambridge, Madingley Road, Cambridge CB3 0ES, UK.
authors: Pietro
authors: P
authors: Mastroeni
authors: Department of Veterinary Medicine, University of Cambridge, Madingley Road, Cambridge CB3 0ES, UK.
authors: Nathalie
authors: N
authors: Ménager
authors: Molecular Microbiology Group, Institute of Food Research, Norwich NR4 7UA, UK.
authors: Matthew
authors: M
authors: Rolfe
authors: Molecular Microbiology Group, Institute of Food Research, Norwich NR4 7UA, UK.
authors: Arthur
authors: A
authors: Thompson
authors: Department of Veterinary Medicine, University of Cambridge, Madingley Road, Cambridge CB3 0ES, UK.
authors: Sanja
authors: S
authors: Ugrinovic
authors: School of Clinical Veterinary Sciences, University of Bristol, Langford House, Langford, Bristol BS40 5DU, UK.
authors: Leanne
authors: L
authors: Sait
authors: School of Clinical Veterinary Sciences, University of Bristol, Langford House, Langford, Bristol BS40 5DU, UK.
authors: Tom
authors: T
authors: Humphrey
authors: Department of Veterinary Medicine, University of Cambridge, Madingley Road, Cambridge CB3 0ES, UK.
authors: Helen
authors: H
authors: Northen
authors: Department of Veterinary Medicine, University of Cambridge, Madingley Road, Cambridge CB3 0ES, UK.
authors: Sarah E
authors: SE
authors: Peters
authors: Department of Veterinary Medicine, University of Cambridge, Madingley Road, Cambridge CB3 0ES, UK.
authors: Duncan J
authors: DJ
authors: Maskell
authors: Molecular Microbiology Group, Institute of Food Research, Norwich NR4 7UA, UK.
authors: Jay C D
authors: JCD
authors: Hinton
authors: Department of Veterinary Medicine, University of Cambridge, Madingley Road, Cambridge CB3 0ES, UK.
authors: Clare E
authors: CE
authors: Bryant
mesh_terms: D000818:Animals; D018929:Cell Culture Techniques; D020869:Gene Expression Profiling; D005798:Genes, Bacterial; D054884:Host-Pathogen Interactions; D051379:Mice; D018384:Oxidative Stress / Q000235:genetics; D012329:RNA, Bacterial / Q000032:analysis / Q000096:biosynthesis / Q000235:genetics; D011971:Receptors, Immunologic / Q000378:metabolism; D012481:Salmonella Infections, Animal / Q000378:metabolism* / Q000382:microbiology; D012486:Salmonella typhimurium / Q000472:pathogenicity / Q000502:physiology*; D015398:Signal Transduction; D013312:Stress, Physiological / Q000235:genetics*; D051197:Toll-Like Receptor 4 / Q000378:metabolism*; D014774:Virulence
chemical_list: C105949:Pirb protein, mouse; D012329:RNA, Bacterial; D011971:Receptors, Immunologic; C493487:Tlr4 protein, mouse; D051197:Toll-Like Receptor 4