Salmonella promotes virulence by repressing cellulose production

Significance Salmonella enterica and a number of phylogenetically distant intracellular bacterial pathogens require the MgtC virulence protein for both intraphagosomal replication and normal growth in magnesium-limited conditions. MgtC operates by interacting with and inhibiting the F ₁F O ATP synthase, reducing ATP levels within the bacterium. We show that by lowering ATP levels, MgtC prevents a rise in cyclic diguanylate, a second messenger that promotes biofilm formation in bacteria. We demonstrate that MgtC represses the biosynthesis of cellulose, a major structural component of Salmonella biofilms, and that cellulose interferes with replication inside macrophages and virulence in mice. Our results indicate that virulence genes can function to repress the expression of traits that interfere with virulence. Cellulose is the most abundant organic polymer on Earth. In bacteria, cellulose confers protection against environmental insults and is a constituent of biofilms typically formed on abiotic surfaces. We report that, surprisingly, Salmonella enterica serovar Typhimurium makes cellulose when inside macrophages. We determine that preventing cellulose synthesis increases virulence, whereas stimulation of cellulose synthesis inside macrophages decreases virulence. An attenuated mutant lacking the mgtC gene exhibited increased cellulose levels due to increased expression of the cellulose synthase gene bcsA and of cyclic diguanylate, the allosteric activator of the BcsA protein. Inactivation of bcsA restored wild-type virulence to the Salmonella mgtC mutant, but not to other attenuated mutants displaying a wild-type phenotype regarding cellulose. Our findings indicate that a virulence determinant can promote pathogenicity by repressing a pathogen's antivirulence trait. Moreover, they suggest that controlling antivirulence traits increases long-term pathogen fitness by mediating a trade-off between acute virulence and transmission.