Enhancement of the anti-Salmonella immune response in CD154-deficient mice by an attenuated, IFN-γ-expressing, strain of Salmonella enterica serovar Typhimurium

Previously, we demonstrated that cell-cell communications via the CD40-CD154 pathway play a critical role in the induction of type 1 cytokine responses, including IL-12 and IFN-γ, which in turn greatly influence the response to Salmonella infections. Mice genetically deficient in the expression of CD154 exhibited markedly increased susceptibility to infection by an attenuated, double auxotrophic (aroA ^-aroD ^-) strain, designated BRD509, of Salmonella enterica Serovar Typhimurium. In the present study, we used a strain of Salmonella engineered to express murine IFN-γ, designated GIDIFN, in order to assess its potential to enhance the host's immune response in CD154-deficient animals. We demonstrate that infection of animals with GIDIFN results in markedly enhanced anti-bacterial response, as evidenced by the significant reduction in bacterial loads in target organs and decreased animal mortality. This was associated with a more robust proinflammatory cytokine response, including IL-6, IL-12, TNF-α and IFN-γ. In protection studies, GIDIFN strain was demonstrably superior than the BRD509 strain in affording protection against virulent Salmonella challenge in naïve CD154 ^-/- mice. Interestingly, however, infection with GIDIFN failed to correct the isotype switching defect in CD154 ^-/- mice, suggesting that the enhanced immunity triggered by GIDIFN strain occurs independently of humoral immune responses. These findings demonstrate that GIDIFN has immunopotentiating effects on the host's immune response and provide direct evidence for the utility of IFN-γ-expressing attenuated Salmonella in enhancement of immune responsiveness in immunodeficient hosts.