A Tale of Twins: The Distinct Roles of Intracellular and Extracellular Formate in Regulating Flagellar and Pathogenicity Island-1 Genes in Salmonella Typhimurium

Host-derived short-chain fatty acids (SCFAs) are extensively being studied for their role in the virulence and pathogenesis of Salmonella Typhimurium (STM). Formate, an SCFA present in the ileum, functions as a signalling molecule to enhance STM invasion. However, the role of intracellular formate in Salmonella virulence remains poorly understood. To investigate this, we generated knockouts of pflB (pyruvate-formate lyase) and focA (formate transporter). Disruption of formate production through pflB deletion led to reduced flagellation and increased hilA and prgH expression, attributed to elevated intracellular pH and membrane damage. This suppression of flagellar machinery drives a shift from adhesion to invasion, regulated by RpoE via the CsrA/csrB pathway. Additionally, we demonstrate that upon compensation for intracellular deficiency of formate, STM{Delta} pflB starts to utilize formate as a signalling molecule to regulate downstream processes. To the best of our knowledge, this study is the first to establish the critical role of the pflB gene in maintaining intracellular pH and controlling virulence gene expression in STM. Lastly, our findings emphasize the importance of modulating pflB expression across intestinal regions to optimize STM invasion. Graphical abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=150 SRC="FIGDIR/small/577997v2_ufig1.gif" ALT="Figure 1"> View larger version (43K): org.highwire.dtl.DTLVardef@1fc5ec3org.highwire.dtl.DTLVardef@1b15b61org.highwire.dtl.DTLVardef@e657caorg.highwire.dtl.DTLVardef@8db00f_HPS_FORMAT_FIGEXP M_FIG C_FIG