Author:
Zigdon Mor,Sawaed Jasmin,Zelik Lilach,Binyamin Dana,Ben-Simon Shira,Asulin Nofar,Levin Rachel,Modilevsky Sonia,Naama Maria,Telpaz Shahar,Rubin Elad,Awad Aya,Sawaed Wisal,Harshuk-Shabso Sarina,Nuriel-Ohayon Meital,Krishnamohan Mathumathi,Werbner Michal,Koren Omry,Winter Sebastian E.,Apte Ron N.,Voronov Elena,Bel Shai
Abstract
Acute gastrointestinal infection with intracellular pathogens like Salmonella Typhimurium triggers the release of the proinflammatory cytokine interleukin 1β (IL-1β). However, the role of IL-1β in intestinal defense against Salmonella remains unclear. Here, we show that IL-1β production is detrimental during Salmonella infection. 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 (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-1β -/- mice which inhibited Salmonella expansion. 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 prevented mortality in Salmonella-infected IL-1β -/- mice. Finally, we found that IL-1β expression correlates with expression of the complement receptor in patients suffering from sepsis, but not uninfected patients and healthy individuals. Thus, Salmonella exploits 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.
Funder
Azrieli Foundation
Israeli Science Foundation
HORIZON EUROPE European Research Council
United States - Israel Binational Science Foundation
Publisher
Public Library of Science (PLoS)
Subject
General Agricultural and Biological Sciences,General Immunology and Microbiology,General Biochemistry, Genetics and Molecular Biology,General Neuroscience