Host inflammation-derived citrate enhances <i>Salmonella</i> Typhimurium pathogenesis by fueling growth and activating virulence.

Abstract

<i>Salmonella enterica</i> serovar Typhimurium (<i>S</i>Tm) infection triggers robust intestinal inflammatory responses during host colonization. Although host inflammatory responses typically function as defense mechanisms, <i>S</i>Tm subverts these processes by co-opting inflammation-derived metabolites to increase both bacterial proliferation and intestinal colonization. Here, we demonstrate that <i>S</i>Tm-induced intestinal inflammation results in the significant accumulation of luminal citrate, which plays dual roles in <i>S</i>Tm pathogenesis, serving as both an anaerobic fermentation substrate to support bacterial growth and a virulence-activating signaling molecule. Mechanistically, the CitAB two-component system detects elevated citrate concentrations in the inflamed intestine, initiating the transcriptional activation of citrate fermentation genes to facilitate <i>S</i>Tm luminal proliferation. Moreover, CitAB-mediated citrate sensing directly upregulates <i>hilD</i>, which encodes the master regulator of <i>Salmonella</i> Pathogenicity Island 1, thereby enhancing type III secretion system-dependent epithelial invasion. Genetic disruption of either citrate anaerobic fermentation pathway or citrate-mediated virulence-regulating pathway severely compromises both intestinal colonization and invasive capacity of <i>S</i>Tm. These findings underscore citrate-responsive pathways as promising therapeutic targets for simultaneously disrupting <i>S</i>Tm metabolic adaptability and virulence.