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.
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We thank J. Schapiro and J. LaPan for biochemical characterization of E. coli O21:H+ and S. Brandt for helpful discussions about the isolate; K. Bodi for helpful advice about whole-genome sequencing analysis; G. Barton, D. Portnoy and K. Barry for helpful discussions and critical reading of the manuscript; E. Kofoed (University of California–Berkeley) for the flaA-IRES-GFP construct; K. Sotelo-Troha for technical help and L. Lopez for support in our mouse facility (University of California–Berkeley). Nlrc4−/− mice were from S. Mariathasan and V. Dixit (Genentech). Casp1−/− mice and S. Typhimurium LT2 ΔfliCΔfljB were a gift from A. Van der Velden and M. Starnbach (Harvard Medical School). Il1b−/− mice were from the Zychlinsky lab at Max Planck Institute. This work was supported in part by US National Institutes of Health grants AI063302, AI075039 and AI080749 awarded to R.E.V. and National Institutes of Health Ruth L. Kirschstein National Research Service Award fellowship AI091068 awarded to J.S.A. R.E.V. is an Investigator of the Cancer Research Institute and a Burroughs Wellcome Fund Investigator in the Pathogenesis of Infectious Disease.
The authors declare no competing financial interests.
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Ayres, J., Trinidad, N. & Vance, R. Lethal inflammasome activation by a multidrug-resistant pathobiont upon antibiotic disruption of the microbiota. Nat Med 18, 799–806 (2012). https://doi.org/10.1038/nm.2729
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