title: Granulocytes impose a tight bottleneck upon the gut luminal pathogen population during Salmonella typhimurium colitis.
abstract: Topological, chemical and immunological barriers are thought to limit infection by enteropathogenic bacteria. However, in many cases these barriers and their consequences for the infection process remain incompletely understood. Here, we employed a mouse model for Salmonella colitis and a mixed inoculum approach to identify barriers limiting the gut luminal pathogen population. Mice were infected via the oral route with wild type S. Typhimurium (S. Tm) and/or mixtures of phenotypically identical but differentially tagged S. Tm strains ("WITS", wild-type isogenic tagged strains), which can be individually tracked by quantitative real-time PCR. WITS dilution experiments identified a substantial loss in tag/genetic diversity within the gut luminal S. Tm population by days 2-4 post infection. The diversity-loss was not attributable to overgrowth by S. Tm mutants, but required inflammation, Gr-1+ cells (mainly neutrophilic granulocytes) and most likely NADPH-oxidase-mediated defense, but not iNOS. Mathematical modelling indicated that inflammation inflicts a bottleneck transiently restricting the gut luminal S. Tm population to approximately 6000 cells and plating experiments verified a transient, inflammation- and Gr-1+ cell-dependent dip in the gut luminal S. Tm population at day 2 post infection. We conclude that granulocytes, an important clinical hallmark of S. Tm-induced inflammation, impose a drastic bottleneck upon the pathogen population. This extends the current view of inflammation-fuelled gut-luminal Salmonella growth by establishing the host response in the intestinal lumen as a double-edged sword, fostering and diminishing colonization in a dynamic equilibrium. Our work identifies a potent immune defense against gut infection and reveals a potential Achilles' heel of the infection process which might be targeted for therapy.
authors.affiliation: Eidgenössische Technische Hochschule Zürich, Institute of Microbiology, Zurich, Switzerland.
authors.forename: Lisa
authors.initials: L
authors.lastname: Maier
authors.affiliation: Eidgenössische Technische Hochschule Zürich, Institute of Microbiology, Zurich, Switzerland.
authors.forename: Médéric
authors.initials: M
authors.lastname: Diard
authors.affiliation: Eidgenössische Technische Hochschule Zürich, Institute of Microbiology, Zurich, Switzerland.
authors.forename: Mikael E
authors.initials: ME
authors.lastname: Sellin
authors.affiliation: Eidgenössische Technische Hochschule Zürich, Institute of Microbiology, Zurich, Switzerland.
authors.forename: Elsa-Sarah
authors.initials: ES
authors.lastname: Chouffane
authors.affiliation: Eidgenössische Technische Hochschule Zürich, Institute of Microbiology, Zurich, Switzerland.
authors.forename: Kerstin
authors.initials: K
authors.lastname: Trautwein-Weidner
authors.affiliation: Eidgenössische Technische Hochschule Zürich, Institute of Microbiology, Zurich, Switzerland.
authors.forename: Balamurugan
authors.initials: B
authors.lastname: Periaswamy
authors.affiliation: Eidgenössische Technische Hochschule Zürich, Institute of Microbiology, Zurich, Switzerland.
authors.forename: Emma
authors.initials: E
authors.lastname: Slack
authors.affiliation: Eidgenössische Technische Hochschule Zürich, Institute of Microbiology, Zurich, Switzerland.
authors.forename: Tamas
authors.initials: T
authors.lastname: Dolowschiak
authors.affiliation: Max von Pettenkofer-Institut, München, Germany; German Center for Infection Research (DZIF), partner site Ludwig Maximilian University of Munich, Munich, Germany.
authors.forename: Bärbel
authors.initials: B
authors.lastname: Stecher
authors.affiliation: Eidgenössische Technische Hochschule Zürich, Institute of Integrative Biology, Zurich, Switzerland.
authors.forename: Claude
authors.initials: C
authors.lastname: Loverdo
authors.affiliation: Eidgenössische Technische Hochschule Zürich, Institute of Integrative Biology, Zurich, Switzerland.
authors.forename: Roland R
authors.initials: RR
authors.lastname: Regoes
authors.affiliation: Eidgenössische Technische Hochschule Zürich, Institute of Microbiology, Zurich, Switzerland.
authors.forename: Wolf-Dietrich
authors.initials: WD
authors.lastname: Hardt
mesh_terms: D000818:Animals; D000900:Anti-Bacterial Agents / Q000627:therapeutic use; D001426:Bacterial Proteins / Q000235:genetics / Q000378:metabolism; D002432:Cecum / Q000378:metabolism / Q000382:microbiology / Q000473:pathology; D003092:Colitis / Q000188:drug therapy / Q000382:microbiology* / Q000473:pathology*; D004195:Disease Models, Animal; D005260:Female; D041981:Gastrointestinal Tract / Q000378:metabolism / Q000382:microbiology* / Q000473:pathology*; D006098:Granulocytes / Q000473:pathology*; D008297:Male; D008565:Membrane Proteins / Q000235:genetics / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D064307:Microbiota / Q000502:physiology; D008962:Models, Theoretical; D009154:Mutation; D012481:Salmonella Infections, Animal / Q000188:drug therapy / Q000382:microbiology / Q000473:pathology*; D012486:Salmonella typhimurium / Q000235:genetics / Q000254:growth & development* / Q000378:metabolism; D013307:Streptomycin / Q000627:therapeutic use
chemical_list: D000900:Anti-Bacterial Agents; D001426:Bacterial Proteins; D008565:Membrane Proteins; C440638:SPI-2 protein, Salmonella; C419942:Spi1 protein, Salmonella; D013307:Streptomycin