Cyclic di-GMP Increases Catalase Production and Hydrogen Peroxide Tolerance in .

is a Gram-negative bacterial pathogen that causes the disease cholera, which affects nearly 1 million people each year. In between outbreaks, resides in fresh and salt water environments, where it is able to persist through changes in temperature, oxygen, and salinity. One key characteristic that promotes environmental persistence of is the ability to form multicellular communities, called biofilms, that often adhere to biotic and abiotic sources. Biofilm formation in is positively regulated by the dinucleotide second messenger cyclic dimeric GMP (c-di-GMP). While most research on the c-di-GMP regulon has focused on biofilm formation or motility, we hypothesized that the c-di-GMP signaling network encompassed a larger set of effector functions than reported. We found that high intracellular c-di-GMP increased catalase activity ∼4-fold relative to strains with unaltered c-di-GMP. Genetic studies demonstrated that c-di-GMP mediated catalase activity was due to increased expression of the catalase-encoding gene Moreover, c-di-GMP mediated regulation of catalase activity and expression required the c-di-GMP dependent transcription factors VpsT and VpsR. Lastly, we found that high c-di-GMP increased survival after HO challenge in a -, -, and -dependent manner. Our results indicate that antioxidant production is regulated by c-di-GMP uncovering a new node in the growing VpsT and VpsR c-di-GMP signaling network of As a result of infection with , patients become dehydrated, leading to death if not properly treated. The aquatic environment is the natural reservoir for , where it can survive alterations in temperature, salinity, and oxygen. The second messenger molecule c-di-GMP is an important signal regulating host and aquatic environmental persistence because it controls whether will form a biofilm or disperse through flagellar motility. In this work, we demonstrate another function of c-di-GMP in biology: promoting tolerance to the reactive oxygen species HO through the differential regulation of catalase expression. Our results suggest a mechanism where c-di-GMP simultaneously controls biofilm formation and antioxidant production, which could promote persistence in human and marine environments.