ID: 224: Stat2-dependent responses lead to increased mortality following Salmonella-induced colitis

Salmonella Typhimurium is an intracellular pathogenic gram-negative bacterium that colonizes predominantly the intestinal lumen, activates Toll-like receptors, and accounts for most of food borne illnesses. The transcription factor Stat2 is vital in type I interferon activated antiviral and antitumor immunity and yet less is known about its role in bacterial infection. In a recent study, we reported that Stat2 was protective when tested in a mouse model of lipopolysaccharide-induced sepsis as mortality was accelerated inStat2 knockout (KO) mice. In this study, we evaluated the effect of Stat2 in a clinically relevant inflammation model of Salmonella-induced colitis. We found that when mice were pretreated with streptomycin and then orally infected with Salmonella, compared to wild type mice, Stat2KO mice showed altered intestinal responses by experiencing lower intestinal bacterial burdens. No differences were found in bacterial burdens at systemic sites. Stat2-dependent responses were lethal to wild type mice while Stat2KO mice were found to be more resistant. In contrast, Stat1KO mice were more susceptible to Salmonella infection than wild type mice suggesting that Stat2 and Stat1 play different roles during pathogenic bacterial infection. Our results indicate that disruption of the intestinal microbiota allows Stat2-dependent responses to play an adverse role in host defense against Salmonella-induced colitis. To our knowledge, this is the first evidence of Stat2 dependent responses playing a negative role in the host defense against pathogenic Salmonella bacteria. Future studies will reveal if this observation applies to other gram negative pathogens.