PhoQ is an unsaturated fatty acid receptor that fine-tunes <i>Salmonella</i> pathogenic traits

Abstract

The <i>Salmonella enterica</i> PhoP/PhoQ two-component signaling system coordinates the spatiotemporal expression of key virulence factors that confer pathogenic traits. Through biochemical and structural analyses, we found that the sensor histidine kinase PhoQ acted as a receptor for long-chain unsaturated fatty acids (LCUFAs), which induced a conformational change in the periplasmic domain of the PhoQ protein. This resulted in the repression of PhoQ autokinase activity, leading to inhibition of the expression of PhoP/PhoQ-dependent genes. Recognition of the LCUFA linoleic acid (LA) by PhoQ was not stereospecific because positional and geometrical isomers of LA equally inhibited PhoQ autophosphorylation, which was conserved in multiple <i>S. enterica</i> serovars. Because orally acquired <i>Salmonella</i> encounters conjugated LA (CLA), a product of the metabolic conversion of LA by microbiota, in the human intestine, we tested how short-term oral administration of CLA affected gut colonization and systemic dissemination in a mouse model of <i>Salmonella</i>-induced colitis. Compared to untreated mice, CLA-treated mice showed increased gut colonization by wild-type <i>Salmonella</i>, as well as increased dissemination to the spleen. In contrast, the inability of the <i>phoP</i> strain to disseminate systemically remained unchanged by CLA treatment. Together, our results reveal that, by inhibiting PhoQ, environmental LCUFAs fine-tune the fate of <i>Salmonella</i> during infection. These findings may aid in the design of new anti-<i>Salmonella</i> therapies.