title: Epithelium-intrinsic NAIP/NLRC4 inflammasome drives infected enterocyte expulsion to restrict Salmonella replication in the intestinal mucosa.
abstract: The gut mucosal epithelium separates the host from the microbiota, but enteropathogens such as Salmonella Typhimurium (S.Tm) can invade and breach this barrier. Defenses against such acute insults remain incompletely understood. Using a murine model of Salmonella enterocolitis, we analyzed mechanisms limiting pathogen loads in the epithelium during early infection. Although the epithelium-invading S.Tm replicate initially, this intraepithelial replicative niche is restricted by expulsion of infected enterocytes into the lumen. This mechanism is compromised if inflammasome components (NAIP1-6, NLRC4, caspase-1/-11) are deleted, or ablated specifically in the epithelium, resulting in ∼100-fold higher intraepithelial loads and accelerated lymph node colonization. Interestingly, the cytokines downstream of inflammasome activation, interleukin (IL)-1α/β and IL-18, appear dispensable for epithelial restriction of early infection. These data establish the role of an epithelium-intrinsic inflammasome, which drives expulsion of infected cells to restrict the pathogen's intraepithelial proliferation. This may represent a general defense mechanism against mucosal infections.
authors.affiliation: Institute of Microbiology, ETH Zürich, 8093 Zürich, Switzerland. Electronic address: msellin@micro.biol.ethz.ch.
authors.forename: Mikael E
authors.initials: ME
authors.lastname: Sellin
authors.affiliation: Institute of Microbiology, ETH Zürich, 8093 Zürich, Switzerland.
authors.forename: Anna A
authors.initials: AA
authors.lastname: Müller
authors.affiliation: Institute of Microbiology, ETH Zürich, 8093 Zürich, Switzerland.
authors.forename: Boas
authors.initials: B
authors.lastname: Felmy
authors.affiliation: Institute of Microbiology, ETH Zürich, 8093 Zürich, Switzerland.
authors.forename: Tamas
authors.initials: T
authors.lastname: Dolowschiak
authors.affiliation: Institute of Microbiology, ETH Zürich, 8093 Zürich, Switzerland.
authors.forename: Médéric
authors.initials: M
authors.lastname: Diard
authors.affiliation: Department of Biochemistry, University of Lausanne, 1066 Epalinges, Switzerland.
authors.forename: Aubry
authors.initials: A
authors.lastname: Tardivel
authors.affiliation: Department of Biochemistry, University of Lausanne, 1066 Epalinges, Switzerland; Laboratory for Intestinal Ecosystem, RIKEN Center for Integrative Medical Sciences (IMS), Yokohama 230-0045, Japan.
authors.forename: Kendle M
authors.initials: KM
authors.lastname: Maslowski
authors.affiliation: Institute of Microbiology, ETH Zürich, 8093 Zürich, Switzerland. Electronic address: hardt@micro.biol.ethz.ch.
authors.forename: Wolf-Dietrich
authors.initials: WD
authors.lastname: Hardt
mesh_terms: D000818:Animals; D051017:Apoptosis Regulatory Proteins / Q000502:physiology*; D002135:Calcium-Binding Proteins / Q000502:physiology*; D002432:Cecum / Q000382:microbiology / Q000473:pathology; D020895:Enterocytes / Q000276:immunology / Q000382:microbiology*; D054884:Host-Pathogen Interactions; D058847:Inflammasomes; D007413:Intestinal Mucosa / Q000276:immunology / Q000382:microbiology / Q000473:pathology; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D051616:Neuronal Apoptosis-Inhibitory Protein / Q000502:physiology*; D012480:Salmonella Infections / Q000276:immunology*; D012486:Salmonella typhimurium / Q000276:immunology*
chemical_list: D051017:Apoptosis Regulatory Proteins; D002135:Calcium-Binding Proteins; D058847:Inflammasomes; C512299:Ipaf protein, mouse; C496801:Naip1 protein, mouse; D051616:Neuronal Apoptosis-Inhibitory Protein