The second messenger cyclic di-GMP (c-di-GMP) enables bacteria to rapidly respond to changes in their environment. Miller and colleagues used a biosensor to measure the levels of intracellular c-di-GMP of Salmonella enterica subsp. enterica serovar Typhimurium during infection of macrophages. Following initial phagocytosis, the intracellular c-di-GMP levels are reduced, and the authors identified three redundant sensor phosphodiesterases that were responsible for maintaining low c-di-GMP concentrations. Deletion of all three enzymes decreased survival of a population of slow-replicating bacteria during macrophage infection, and deletion of the cellulose synthase machinery restored virulence in mutant bacteria lacking enzymatic activity, which suggests that low c-di-GMP concentrations prevent the overproduction of cellulose. The authors hypothesized that glucose limitation in the intracellular environment drives the reduction of cellulose production and promotes survival.