Salmonella- infected superspreader hosts require gut regulatory T cells to maintain an asymptomatic state during chronic infection 3938

Description Salmonella Typhimurium (STm) is an intracellular enteric pathogen that causes gastroenteritis in humans and Typhoid fever-like symptoms in mice. Oral infection of 129X1/SvJ mice with STm results in ∼30% of the mice being high shedder (>108 STm CFU/g feces) even after 4 weeks post-infection. Since these animals can rapidly transmit Salmonella to a naïve host, we refer to them as superspreaders (SSP). Unexpectedly, SSP mice are asymptomatic carriers despite a persistent high-pathogen burden in the feces and a robust intestinal type-1 response even at 28 days post-infection. We found that SSP mice are disease tolerant due to an increased colonic regulatory T cell (Treg) population characterized by a unique transcriptomic profile with upregulated type 1 inflammatory genes, including the transcription factor T-bet. Ablation of Tregs in SSP mice resulted in a dramatic weight loss, increased gut inflammation, and a compromised epithelial intestinal barrier. Notably, bacterial burden was unchanged in Treg-depleted SSP mice, suggesting that morbidity was not caused by increased pathogen burden. In absence of Tregs, we observed robust expansion of cytotoxic CD4+ T cells, whose depletion restored homeostasis in SSP mice, confirming that the disease state was caused by immune pathology. These results reveal how hosts mitigate inflammation during chronic enteric infections, providing insights into the management of persistent infections and long-lasting intestinal inflammatory conditions. Funding Sources Supported by Defense Advanced Research Project Agency (DARPA) Grant DARPA-15-21-THoR-FP-006, 5R01-AI11605906 from NIAID, and 5R01-AI13124903 from NIAID.