The outcome of infection with Salmonella Typhimurium in mouse models of human typhoid fever, is dependent upon a coordinated complex immune response. A panel of recombinant congenic strains (RCS) derived from reciprocal double backcross of A/J and C57BL/6J mice has been screened for their susceptibility to Salmonella infection, and two susceptibility loci, Ity4 (Immunity to Typhimurium locus 4) and Ity5 were identified. We validated Ity5 in a genetic environment free of the impact of Ity4 using a cross between A/J and 129S6. Using a time-series analysis of genome-wide transcription during the first 7 days post-infection, comparing A/J mice to AcB60 control mice having a C57BL/6J derived Ity5 interval, we have identified the differential expression of the Ity5 positional candidate gene Cd40, Cd40 associated canonical signaling pathways, and the differential expression of numerous genes involved in neutrophil function. CD40 is known to coordinate T-cell dependent B cell responses and myeloid cell activation. In fact, CD40 signaling is altered in A/J mice as seen by impaired IgM upregulation during infection, decreased Ig class switching, and reduced granulocyte recruitment in response to infection and inflammation. Defective granulocyte recruitment in A/J mice was associated with decreased ERK-1/2 activity. These results suggest that altered Cd40 signaling and granulocyte recruitment in response to infection are responsible for the Ity5 associated susceptibility to Salmonella infection of A/J mice.