PhoQ is an unsaturated fatty acid receptor that fine-tunes Salmonella pathogenic traits

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.

Long Chain Fatty Acids and Virulence Repression in Intestinal Bacterial Pathogens

“…However, the administration of a CLA supplement failed to attenuate S. Typhimurium gut infection or systemic dissemination in the streptomycin infection model (Carabajal et al, 2020). Subsequent studies demonstrated that the periplasmic sensor domain in PhoQ likely interacts with various LCUFAs to inhibit its autophosphorylation (Carabajal et al, 2020). (Figure 2B) Finally, in addition to its phosphorylation by PhoQ, recent work has demonstrated that PhoP DNA binding activity is further modulated by the acetylation of lysine residues within its DNA binding domain (Ren et al, 2016;Li et al, 2021).…”

“…Accordingly, the HK receptor PhoQ becomes autophosphorylated in response to various environmental signals including moderate acid stress, osmotic stress, low Mg 2+ availability, and CAMPs (Fields et al, 1986;Fields et al, 1989). More recently, a screen of potential plant-derived inhibitors of PhoQ identified LCUFAs, and not saturated LCFAs, as exogenous signals that inhibit autokinase activity in PhoQ and repress PhoP regulated genes (Gastoń et al, 2013;Carabajal et al, 2020). Interestingly, this included conjugated linoleic acids (CLAs), which are common products of bacterial biotransformation reactions that occur in the gut.…”

“…Interestingly, this included conjugated linoleic acids (CLAs), which are common products of bacterial biotransformation reactions that occur in the gut. However, the administration of a CLA supplement failed to attenuate S. Typhimurium gut infection or systemic dissemination in the streptomycin infection model (Carabajal et al, 2020). Subsequent studies demonstrated that the periplasmic sensor domain in PhoQ likely interacts with various LCUFAs to inhibit its autophosphorylation (Carabajal et al, 2020).…”

Lipid Species in the GI Tract are Increased by the Commensal Fungus Candida albicans and Decrease the Virulence of Clostridioides difficile

“…Additionally, oleic acid induced oxidative stress responses in C. albicans and displayed broad effects, which included the modification of the ergosterol composition on the fungal cell membrane although the exact effects in an animal model are not known. A related unsaturated fatty acid, linoleic acid, has recently been shown to enhance Salmonella enterica gastrointestinal colonization dissemination to the spleen in a murine model [74]. Both of these studies suggest that lipids could play a complex role in the host gastrointestinal tract, providing beneficial or detrimental effects to the host, possibly influenced by the overall microbiota composition and state of the host immune response.…”

Effect-Directed Synthesis of PhoP/PhoQ Inhibitors to Regulate Salmonella Virulence

“…However, only a handful of inhibitors are known to selectively target the Salmonella PhoP/PhoQ regulatory system in vitro . They include two quinazoline-based compounds, which target PhoQ histidine kinase activity, and some unsaturated fatty acids. − Interestingly, a modulatory effect of long-chain polyunsaturated fatty acids along Salmonella infection has been observed in mice …”