Understanding succinate sensing and transport as regulators of Salmonella Typhimurium virulence

Intracellular bacteria need to adapt to their host hostile environment in order to survive and replicate. Our lab has recently found that while the host immunometabolite succinate is required for activation of macrophages antimicrobial defenses, Salmonella Typhimurium has evolved to sense and respond to host succinate accumulation as a signal inducing its own intracellular virulence programs. We revealed that DcuB, a C4-dicarboxylates transporter, mediates bacterial succinate uptake and intracellular survival. Nevertheless, we still don`t know what are the molecular mechnisms that underlie succinate metabolismin in the crosstalk between the host cells and Salmonella and how it changes Salmonella virulence. In order to both monitor the metabolic changes sensed by Salmonella and decipher the role of DcuB in succinate-mediated virulence during macrophage infection, we have developed a dcuB expression reporter that acts as a succinate biosensor. We show that this reporter is up-regulated by succinate and anaerobic conditions, and its intramacrophage expression is correlated to the accumulation of host succinate. Furthermore, we have identified a hypothetical peptide located up-stream to the dcuB gene and is unique to Salmonella species. We hypothesize that it is involved in dcuB expression regulation via succinate signalling. In the future, we will use this tool to study the molecular mechanisms responsible for succinate signaling. We expect that understanding the molecular mechanisms underlying succinate sensing and succinate-induced virulence will provide insights into the new realm of host-pathogen metabolic crosstalk.