title: Lethal inflammasome activation by a multidrug-resistant pathobiont upon antibiotic disruption of the microbiota.
abstract: The mammalian intestine harbors a complex microbial community that provides numerous benefits to its host. However, the microbiota can also include potentially virulent species, termed pathobiont, which can cause disease when intestinal homeostasis is disrupted. The molecular mechanisms by which pathobionts cause disease remain poorly understood. Here we describe a sepsis-like disease that occurs upon gut injury in antibiotic-treated mice. Sepsis was associated with the systemic spread of a specific multidrug-resistant Escherichia coli pathobiont that expanded markedly in the microbiota of antibiotic-treated mice. Rapid sepsis-like death required a component of the innate immune system, the Naip5-Nlrc4 inflammasome. In accordance with Koch's postulates, we found the E. coli pathobiont was sufficient to activate Naip5-Nlrc4 and cause disease when injected intravenously into unmanipulated mice. These findings reveal how sepsis-like disease can result from recognition of pathobionts by the innate immune system.
authors.affiliation: Department of Molecular & Cell Biology, Division of Immunology & Pathogenesis, University of California, Berkeley, USA. jayres@berkeley.edu
authors.forename: Janelle S
authors.initials: JS
authors.lastname: Ayres
authors.forename: Norver J
authors.initials: NJ
authors.lastname: Trinidad
authors.forename: Russell E
authors.initials: RE
authors.lastname: Vance
mesh_terms: D000818:Animals; D000900:Anti-Bacterial Agents / Q000494:pharmacology*; D051017:Apoptosis Regulatory Proteins / Q000502:physiology*; D002135:Calcium-Binding Proteins / Q000502:physiology*; D024901:Drug Resistance, Multiple, Bacterial; D004926:Escherichia coli / Q000187:drug effects*; D007113:Immunity, Innate; D058847:Inflammasomes / Q000502:physiology*; D007422:Intestines / Q000382:microbiology*; D054892:Metagenome / Q000187:drug effects*; D051379:Mice; D008810:Mice, Inbred C57BL; D051616:Neuronal Apoptosis-Inhibitory Protein / Q000502:physiology*; D018805:Sepsis / Q000209:etiology; D037521:Virulence Factors / Q000032:analysis
chemical_list: D000900:Anti-Bacterial Agents; D051017:Apoptosis Regulatory Proteins; D002135:Calcium-Binding Proteins; D058847:Inflammasomes; C512299:Ipaf protein, mouse; C496806:Naip5 protein, mouse; D051616:Neuronal Apoptosis-Inhibitory Protein; D037521:Virulence Factors