The Cytokine IL-22 Promotes Pathogen Colonization by Suppressing Related Commensal Bacteria

Abstract

Summary Interleukin-22 (IL-22) is highly induced in response to infections with a variety of pathogens and its main functions are considered to be tissue repair and host defense at mucosal surfaces. Here we show that IL-22 has a previously undiscovered role during infection in that its expression suppresses the intestinal microbiota and enhances the colonization of a pathogen. IL-22 induced the expression of antimicrobial proteins, including lipocalin-2 and calprotectin, which sequester metal ions from microbes. As Salmonella Typhimurium overcomes metal starvation by lipocalin-2 and calprotectin, IL-22 boosted this pathogen’s colonization of the inflamed intestine by suppressing commensal Enterobacteriaceae, which in the absence of IL-22 overgrew S. Typhimurium. Thus, IL-22 expression can tip the balance between pathogenic and commensal bacteria in favor of a pathogen. Taken together, IL-22 induction can be exploited by pathogens to suppress the growth of their closest competitors, thereby enhancing pathogen colonization of mucosal surfaces.

Salmonella Typhimurium utilizes a T6SS-mediated antibacterial weapon to establish in the host gut

“…We first tested the ability of WT or SPI-6-deficient strains to kill representative commensals of the gut microbiota in vitro. Using the conditions described above, we show that S. Typhimurium kills K. oxytoca and Klebsiella variicola in a SPI-6-dependent manner, but not Enterobacter cloacae or the E. coli JB2 mouse commensal strain (28) (Fig. 2B).…”

“…Previous studies on the mechanisms of S. Typhimurium colonization of the mouse gut have shown that Salmonella exploits intestinal inflammation to compete with the resident microbiota and to thrive in the inflamed gut (28)(29)(30)(31)(32). All these previous studies have been performed in mice that have been pretreated with an antibiotic (e.g., streptomycin) that perturbs the indigenous microbiota.…”

“…coli JB2 commensal strain was kindly provided by M. Raffatellu, University of California, Irvine, CA (28). Commensal bacterial strains used in this study were isolated from WT C57BL/6 and 129x1/SvJ mice housed at Stanford University (Table S1).…”

“…This not only illustrates the critical role of the intestinal microbiota in modulating Salmonella infection, but also suggests that Salmonella must modulate its interactions with the microbiota (27). Several reports have shown that acute inflammation triggered by S. Typhimurium modifies the gut bacterial community to facilitate pathogen colonization in a mouse model (28)(29)(30)(31)(32). However, it is currently unknown whether Salmonella can directly target commensal bacteria with an antibacterial activity.…”

Antimicrobial lipids: Emerging effector molecules of innate host defense

“…It is possible that the liberation of antibacterial linoleic acid is primarily targeted against other bacteria thereby conferring growth advantage to S. aureus. Such a mechanism has been proposed for Salmonella where the bacteria induce the production of antimicrobial proteins in the intestine that in turn altered the normal microbiota facilitating infection with the pathogen [90] . Successful pathogens subvert host defense mechanisms that normally control infection.…”