STAT2 dependent Type I Interferon response promotes dysbiosis and luminal expansion of the enteric pathogen Salmonella Typhimurium.

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 IFN 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. Author summary The spread of invading microbes is frequently contained by an inflammatory response. Yet, some pathogenic microbes have evolved to utilize inflammation for niche generation and to support their metabolism. Here, we demonstrate that S. Typhimurium exploits type I IFN signaling, a prototypical anti-viral response, to foster its own growth in the inflamed gut. In the absence of STAT2-dependent type I IFN, production of neutrophil reactive oxygen species was impaired, and epithelial metabolism returned to homeostatic hypoxia. Consequently, S. Typhimurium was unable to respire in the absence of type I IFN, and failed to expand in the gut lumen. Furthermore, perturbation of the gut microbiota was dependent on type I IFN signaling. Taken together, our work suggests that S. Typhimurium utilizes STAT2-dependent type I IFN signaling to generate a niche in the inflamed intestinal tract and outcompete the gut microbiota.