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How Salmonella senses the gut
Salmonella enterica commonly causes gastroenteritis, but it can also disseminate from the gut to cause invasive infections and bacteremia. The two-component system comprising the sensor histidine kinase PhoQ and the cytoplasmic response regulator PhoP controls the expression of many Salmonella virulence genes. Carabajal et al. found that long-chain unsaturated fatty acids (LCUFAs), such as those found in the gut and in bile, directly inhibited the autokinase activity of PhoQ and reduced the expression of PhoP-activated genes in various S. enterica serovars. Oral administration of conjugated linoleic acid (CLA) enhanced both gut colonization and dissemination of Salmonella to the spleen. Thus, the detection of LCUFAs by PhoQ enables Salmonella to modify its virulence gene expression program for optimal colonization of the gut niche.
Abstract
The Salmonella enterica 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 S. enterica serovars. Because orally acquired Salmonella 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 Salmonella-induced colitis. Compared to untreated mice, CLA-treated mice showed increased gut colonization by wild-type Salmonella, as well as increased dissemination to the spleen. In contrast, the inability of the phoP strain to disseminate systemically remained unchanged by CLA treatment. Together, our results reveal that, by inhibiting PhoQ, environmental LCUFAs fine-tune the fate of Salmonella during infection. These findings may aid in the design of new anti-Salmonella therapies.
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