Salmonella Mitigates Oxidative Stress and Thrives in the Inflamed Gut by Evading Calprotectin-Mediated Manganese Sequestration

Neutrophils hinder bacterial growth by a variety of antimicrobial mechanisms, including the production of reactive oxygen species and the secretion of proteins that sequester nutrients essential to microbes. A major player in this process is calprotectin, a host protein that exerts antimicrobial activity by chelating zinc and manganese. Here we show that the intestinal pathogen Salmonella enterica serovar Typhimurium uses specialized metal transporters to evade calprotectin sequestration of manganese, allowing the bacteria to outcompete commensals and thrive in the inflamed gut. The pathogen’s ability to acquire manganese in turn promotes function of SodA and KatN, enzymes that use the metal as a cofactor to detoxify reactive oxygen species. This manganese-dependent SodA activity allows the bacteria to evade neutrophil killing mediated by calprotectin and reactive oxygen species. Thus, manganese acquisition enables S. Typhimurium to overcome host antimicrobial defenses and support its competitive growth in the intestine. [Display omitted] •Salmonella acquires manganese (Mn) to resist neutrophil responses in the inflamed gut•Mn uptake helps Salmonella resist calprotectin-enhanced oxidative stress•Mn-dependent antioxidant enzymes promote Salmonella growth in the inflamed gut•Salmonella outcompetes commensal E. coli in the inflamed gut by acquiring Mn Neutrophils hinder bacterial growth by producing reactive oxygen species and proteins that sequester nutrients, such as manganese. Diaz-Ochoa et al. demonstrate that Salmonella Typhimurium overcomes manganese sequestration through transporters that supply this metal to bacterial manganese-dependent antioxidant enzymes, which mitigate neutrophil-derived oxidative stress and facilitate survival in the inflamed gut.