Enhanced <em>Salmonella</em> mortality in naturally resistant, immunocompetent male mice is associated with an altered systemic immune response

While typhoid fever affects both sexes at an equal rate, males are at higher risk for intestinal perforation, which increases mortality. The mechanisms behind the increased morbidity of typhoid fever in human males remain an important but understudied question. Using a 129X1/SvJ [NRAMP+/+ (SLC11A1)] murine model of typhoid chronic infection, we determined that males in this model exhibit increased bacterial burden and mortality in comparison to females (median survival 7 vs. 11 days-post infection, respectively). This decreased survival in males was influenced by the diet preceding infection, as male mice fed a lithogenic diet, to induce gallstones, important to chronic infection, or a normal diet had a lower median survival time, although no difference in overall probability of survival. We also explored how the systemic immune response may contribute to increased mortality by comparing serum cytokine levels between males and females. Males had higher overall levels of pro-inflammatory cytokines and IL-10 and lower levels of IL-27, which are known to inhibit the protective responses to Salmonella infection. Together, we present the first report that the 129X1/SvJ murine model of Salmonella infection responds to infection in a sex-dependent manner, characterized by maladjusted systemic cytokine production and increased bacterial burden in males.