Nlrc4 inflammasome is critical for host protection against flagellated Salmonella

Salmonella enterica serovar Typhimurium is a leading cause of gastroenteritis worldwide and a deadly pathogen in children, immunocompromised patients, and the elderly. Salmonella induces innate immune responses through the Nlrc4 inflammasome, which has been demonstrated to have distinct roles during systemic and mucosal detection of flagellin and non-flagellin molecules. We hypothesized that Nlrc4 recognition of Salmonella flagellin is the dominant protective pathway during infection. To test this hypothesis, we used wild-type, flagellin-deficient, and flagellin-overproducing Salmonella to establish the role of flagellin in mediating Nlrc4-dependent host resistance during systemic and mucosal infection. We observed that during the systemic phase of infection, Salmonella efficiently evades Nlrc4-mediated innate immunity. However, during mucosal Salmonella infection, flagellin recognition by the Nlrc4 inflammasome pathway is the dominant mediator of protective innate immunity. These data establish that recognition of Salmonella’s flagellin by the Nlrc4 inflammasome during mucosal infection is the dominant innate protective pathway for host resistance against the enteric pathogen.