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Wilson RP , Tursi SA , Rapsinski GJ , Medeiros NJ , Le LS , Kotredes KP , Patel S , Liverani E , Sun S , Zhu W , Kilpatrick L , Winter SE , Gamero AM , Tukel C
STAT2 dependent Type I Interferon response promotes dysbiosis and luminal expansion of the enteric pathogen Salmonella Typhimurium
PLoS Pathog. 2019 Apr 22;15(4) :e1007745
PMID: 31009517    PMCID: PMC6513112    URL: https://www.ncbi.nlm.nih.gov/pubmed/31009517
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The mechanisms by which the gut luminal environment is disturbed by the immune system to foster pathogenic bacterial growth and survival remain incompletely understood. Here, we show that STAT2 dependent type I IFN signaling contributes to the inflammatory environment by disrupting hypoxia enabling the pathogenic S. Typhimurium to outgrow the microbiota. Stat2-/- mice infected with S. Typhimurium exhibited impaired type I IFN induced transcriptional responses in cecal tissue and reduced bacterial burden in the intestinal lumen compared to infected wild-type mice. Although inflammatory pathology was similar between wild-type and Stat2-/- mice, we observed decreased hypoxia in the gut tissue of Stat2-/- mice. Neutrophil numbers were similar in wild-type and Stat2-/- mice, yet Stat2-/- mice showed reduced levels of myeloperoxidase activity. In vitro, the neutrophils from Stat2-/- mice produced lower levels of superoxide anion upon stimulation with the bacterial ligand N-formylmethionyl-leucyl-phenylalanine (fMLP) in the presence of IFNalpha compared to neutrophils from wild-type mice, indicating that the neutrophils were less functional in Stat2-/- mice. Cytochrome bd-II oxidase-mediated respiration enhances S. Typhimurium fitness in wild-type mice, while in Stat2-/- deficiency, this respiratory pathway did not provide a fitness advantage. Furthermore, luminal expansion of S. Typhimurium in wild-type mice was blunted in Stat2-/- mice. Compared to wild-type mice which exhibited a significant perturbation in Bacteroidetes abundance, Stat2-/- mice exhibited significantly less perturbation and higher levels of Bacteroidetes upon S. Typhimurium infection. Our results highlight STAT2 dependent type I IFN mediated inflammation in the gut as a novel mechanism promoting luminal expansion of S. Typhimurium.
1553-7374 Wilson, R Paul Tursi, Sarah A Rapsinski, Glenn J Medeiros, Nicole J ORCID: http://orcid.org/0000-0003-4449-2441 Le, Long S Kotredes, Kevin P ORCID: http://orcid.org/0000-0001-7874-4139 Patel, Sajan Liverani, Elisabetta ORCID: http://orcid.org/0000-0001-5540-0456 Sun, Shuang Zhu, Wenhan Kilpatrick, Laurie ORCID: http://orcid.org/0000-0002-2554-507X Winter, Sebastian E Gamero, Ana M ORCID: http://orcid.org/0000-0001-7843-1415 Tukel, Cagla ORCID: http://orcid.org/0000-0001-7073-0226 Journal Article United States PLoS Pathog. 2019 Apr 22;15(4):e1007745. doi: 10.1371/journal.ppat.1007745.