Abstract
AbstractAcute gastrointestinal infection with intracellular pathogens likeSalmonellaTyphimurium triggers the inflammasome and the release of the proinflammatory cytokine interleukin 1β (IL-1β). However, the role of IL-1β in intestinal defense againstSalmonellaremains unclear. Here, we show that IL-1β production is detrimental duringSalmonellainfection. Mice lacking IL-1β (IL-1β-/-) 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 infectedIL-1β-/-mice which inhibitedSalmonellaexpansion. Additionally, we found that IL-1β induces expression of complement anaphylatoxins and suppresses the complement-inactivator Carboxypeptidase N (CPN1). Disrupting this process via IL-1β loss completely prevented mortality inSalmonella-infectedIL-1β-/-mice and led to chronic infection. Thus,Salmonellaexploits IL-1β signaling to outcompete commensal microbes and establish gut colonization. Moreover, our findings identify the intersection of IL-1β signaling and the complement system as key host factors involved in controlling mortality during invasive Salmonellosis.
Publisher
Cold Spring Harbor Laboratory