Salmonella manipulates the host to drive pathogenicity via induction of interleukin 1β

Abstract

Acute gastrointestinal infection with intracellular pathogens like Salmonella Typhimurium triggers the inflammasome and the release of the proinflammatory cytokine interleukin 1{beta} (IL-1{beta}). However, the role of IL-1{beta} in intestinal defense against Salmonella remains unclear. Here, we show that IL-1{beta} production is detrimental during Salmonella infection. Mice lacking IL-1{beta} (IL-1{beta} -/-) failed to recruit neutrophils to the gut during infection, which reduced tissue damage and prevented depletion of short-chain fatty acid-producing commensals. Changes in epithelial cell metabolism that typically support pathogen expansion, such as switching energy production from fatty acid oxidation to fermentation, were absent in infected IL-1{beta}-/- mice which inhibited Salmonella expansion. Additionally, we found that IL-1{beta} induces expression of complement anaphylatoxins and suppresses the complement-inactivator Carboxypeptidase N (CPN1). Disrupting this process via IL-1{beta} loss completely prevented mortality in Salmonella-infected IL-1{beta}-/- mice and led to chronic infection. Thus, Salmonella exploits IL-1{beta} signaling to outcompete commensal microbes and establish gut colonization. Moreover, our findings identify the intersection of IL-1{beta} signaling and the complement system as key host factors involved in controlling mortality during invasive Salmonellosis.