A response regulator promotes Francisella tularensis intramacrophage growth by repressing an anti‐virulence factor

Summary The orphan response regulator PmrA is essential for the intramacrophage growth and survival of Francisella tularensis. PmrA was thought to promote intramacrophage growth by binding directly to promoters on the Francisella Pathogenicity Island (FPI) and positively regulating the expression of FPI genes, which encode a Type VI secretion system required for intramacrophage growth. Using both ChIP‐Seq and RNA‐Seq we identify those regions of the F. tularensis chromosome occupied by PmrA and those genes that are regulated by PmrA. We find that PmrA associates with 252 distinct regions of the F. tularensis chromosome, but exerts regulatory effects at only a few of these locations. Rather than by functioning directly as an activator of FPI gene expression we present evidence that PmrA promotes intramacrophage growth by repressing the expression of a single target gene we refer to as priM (PmrA‐repressed inhibitor of intramacrophage growth). Our findings thus indicate that the role of PmrA in facilitating intracellular growth is to repress a previously unknown anti‐virulence factor. PriM is the first bacterially encoded factor to be described that can interfere with the intramacrophage growth and survival of F. tularensis. It was thought that the response regulator PmrA was essential for the intramacrophage growth of Francisella tularensis because it positively regulated the expression of type VI secretion genes present on the so‐called Francisella Pathogenicity Island. We show instead that PmrA promotes intramacrophage growth by repressing a gene that encodes a previously unknown anti‐virulence factor. This PmrA‐repressed gene is the first F. tularensis gene we are aware of that can interfere with intramacrophage growth and survival.