Uncoupling of invasive bacterial mucosal immunogenicity from pathogenicity

Non-typhoidal Salmonella and other enteric infections are associated with innate immunity-driven inflammatory responses and pathology. The vigorous immune response induced by a virulent pathogen generally leads to more efficacious mucosal immunity than exposure to an avirulent strain. Whether the associated inflammation stimulus is necessary or redundant for the induction of functional adaptive immunity is unclear and has been difficult to address experimentally. Here we show that live bacterial virulence factor-driven superior functional immunogenicity can be uncoupled from concomitant inflammatory pathology. We used a novel quantitative infection model of auxotrophic Salmonella enterica mutants in germ-free animals to dissect the bacterial parameters contributing to immunogenicity. Although mucosal Salmonella virulence factor function in this model no longer caused marked innate inflammatory responses, it remained the main driver of protective mucosal immunity. Isogenic virulence factor-deficient, like chemically inactivated, bacteria were significantly impaired in their protective immunogenicity. Despite their known functions in Salmonella-induced innate immunity, innate pattern recognition receptor signaling pathways through MYD88 and TRIF, Caspase-1 and -11, NLRC4, and NOD1 and -2 were redundant in vivo for the robust live Salmonella-induced mucosal adaptive immunity. These findings reveal exquisite system redundancy between the inductive mechanisms of innate and adaptive mucosal immunity that allows robust pathogen recognition and may be exploitable for the vaccination in innate immunodeficient individuals.