title: Energy Taxis toward Host-Derived Nitrate Supports a Salmonella Pathogenicity Island 1-Independent Mechanism of Invasion.
abstract: Salmonella enterica serovar Typhimurium can cross the epithelial barrier using either the invasion-associated type III secretion system (T3SS-1) or a T3SS-1-independent mechanism that remains poorly characterized. Here we show that flagellum-mediated motility supported a T3SS-1-independent pathway for entering ileal Peyer's patches in the mouse model. Flagellum-dependent invasion of Peyer's patches required energy taxis toward nitrate, which was mediated by the methyl-accepting chemotaxis protein (MCP) Tsr. Generation of nitrate in the intestinal lumen required inducible nitric oxide synthase (iNOS), which was synthesized constitutively in the mucosa of the terminal ileum but not in the jejunum, duodenum, or cecum. Tsr-mediated invasion of ileal Peyer's patches was abrogated in mice deficient for Nos2, the gene encoding iNOS. We conclude that Tsr-mediated energy taxis enables S Typhimurium to migrate toward the intestinal epithelium by sensing host-derived nitrate, thereby contributing to invasion of Peyer's patches.
  
  
  
  Nontyphoidal Salmonella serovars, such as S. enterica serovar Typhimurium, are a common cause of gastroenteritis in immunocompetent individuals but can also cause bacteremia in immunocompromised individuals. While the invasion-associated type III secretion system (T3SS-1) is important for entry, S Typhimurium strains lacking a functional T3SS-1 can still cross the intestinal epithelium and cause a disseminated lethal infection in mice. Here we observed that flagellum-mediated motility and chemotaxis contributed to a T3SS-1-independent pathway for invasion and systemic dissemination to the spleen. This pathway required the methyl-accepting chemotaxis protein (MCP) Tsr and energy taxis toward host-derived nitrate, which we found to be generated by inducible nitric oxide synthase (iNOS) in the ileal mucosa prior to infection. Collectively, our data suggest that S Typhimurium enhances invasion by actively migrating toward the intestinal epithelium along a gradient of host-derived nitrate emanating from the mucosal surface of the ileum.
authors.affiliation: Department of Medical Microbiology and Immunology, School of Medicine, University of California at Davis, Davis, California, USA.
authors.forename: Fabian
authors.initials: F
authors.lastname: Rivera-Chávez
authors.affiliation: Department of Medical Microbiology and Immunology, School of Medicine, University of California at Davis, Davis, California, USA.
authors.forename: Christopher A
authors.initials: CA
authors.lastname: Lopez
authors.affiliation: Department of Medical Microbiology and Immunology, School of Medicine, University of California at Davis, Davis, California, USA.
authors.forename: Lillian F
authors.initials: LF
authors.lastname: Zhang
authors.affiliation: Departamento de Genética, Universidad de Sevilla, Seville, Spain.
authors.forename: Lucía
authors.initials: L
authors.lastname: García-Pastor
authors.affiliation: Department of Medical Microbiology and Immunology, School of Medicine, University of California at Davis, Davis, California, USA.
authors.forename: Alfredo
authors.initials: A
authors.lastname: Chávez-Arroyo
authors.affiliation: Department of Medical Microbiology and Immunology, School of Medicine, University of California at Davis, Davis, California, USA.
authors.forename: Kristen L
authors.initials: KL
authors.lastname: Lokken
authors.affiliation: Department of Medical Microbiology and Immunology, School of Medicine, University of California at Davis, Davis, California, USA.
authors.forename: Renée M
authors.initials: RM
authors.lastname: Tsolis
authors.affiliation: Department of Microbiology, University of Texas Southwestern Medical Center, Dallas, Texas, USA.
authors.forename: Sebastian E
authors.identifier: 0000-0003-1532-9178
authors.initials: SE
authors.lastname: Winter
authors.affiliation: Department of Medical Microbiology and Immunology, School of Medicine, University of California at Davis, Davis, California, USA ajbaumler@ucdavis.edu.
authors.forename: Andreas J
authors.initials: AJ
authors.lastname: Bäumler
mesh_terms: D000818:Animals; D001426:Bacterial Proteins / Q000378:metabolism*; D002432:Cecum / Q000201:enzymology; D002633:Chemotaxis; D004195:Disease Models, Animal; D004705:Endocytosis; D004734:Energy Metabolism; D004847:Epithelial Cells / Q000382:microbiology*; D005407:Flagella / Q000502:physiology; D044404:Genomic Islands; D007421:Intestine, Small / Q000201:enzymology; D008124:Locomotion; D008565:Membrane Proteins / Q000378:metabolism*; D051379:Mice; D009566:Nitrates / Q000378:metabolism*; D052247:Nitric Oxide Synthase Type II / Q000032:analysis; D012480:Salmonella Infections / Q000382:microbiology*; D012486:Salmonella typhimurium / Q000378:metabolism / Q000472:pathogenicity* / Q000502:physiology
chemical_list: D001426:Bacterial Proteins; D008565:Membrane Proteins; D009566:Nitrates; C057635:Tsr protein, Bacteria; D052247:Nitric Oxide Synthase Type II; C496317:Nos2 protein, mouse