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

Acute gastrointestinal infection with intracellular pathogens like Salmonella Typhimurium triggers 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 (SCFA)-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 prevented mortality in Salmonella-infected IL-1 beta( -/- )mice. Finally, we found that IL-1 beta expression correlates with expression of the complement receptor in patients suffering from sepsis, but not uninfected patients and healthy individuals. 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.