THE STRINGENT RESPONSE REGULATOR DKSA IS REQUIRED FOR SALMONELLA TYPHIMURIUM GROWTH IN MINIMAL MEDIA, MOTILITY, BIOFILM FORMATION AND INTESTINAL COLONIZATION

Salmonella enterica serovar Typhimurium is a facultative intracellular human and animal bacterial pathogen posing a major threat to public health worldwide. Salmonella pathogenicity requires complex coordination of multiple physiological and virulence pathways. DksA is a conserved Gram-negative regulator, belongs to a distinct group of transcription factors that bind directly to the RNA polymerase secondary channel, potentiating the effect of the signaling molecule ppGpp during a stringent response. Here, we established that in S. Typhimurium, dksA is induced during the logarithmic phase and that DksA is essential for growth in minimal defined media and plays an important role in motility and biofilm formation. Furthermore, we demonstrate that DksA positively regulates the Salmonella pathogenicity Island-1 and motility-chemotaxis genes and is necessary for S. Typhimurium invasion into human epithelial cells and uptake by macrophages. In contrast, DksA was found to be dispensable for S. Typhimurium host cell adhesion. Finally, using the colitis mouse model, we show that dksA is spatially induced at the mid-cecum during the early stage of the infection and required for gastrointestinal colonization and systemic infection in-vivo. Taken together, these data indicate that the ancestral stringent response regulator, DksA coordinates various physiological and virulence S. Typhimurium programs and therefore is a key virulence regulator of Salmonella.