ABSTRACT Infection induced host cell stress underlies many host-pathogen engagements, yet the mechanisms by which host cell stress influences the innate immune response to infection remain poorly understood. The Integrated Stress Response (ISR) is an evolutionally conserved intracellular signaling pathway allowing cells to adapt to environmental and pathological conditions. Upon activation of one or more of the four stress sensing kinases, the signaling cascade converges into one central pathway and the ISR quickly controls cellular programming through transcriptional and translational regulation to stimulate cellular repair, metabolic reprogramming, and cell to cell signaling in an effort to return to homeostasis. My preliminary data demonstrate that the human adapted pathogen, Salmonella enterica serovar Typhi (STY), activates the murine macrophage ISR during infection. As the causative agent of typhoid fever, STY is a global health burden with millions of cases per year and tens to hundreds of thousands of deaths annually. By using a maladapted host model of infection, this research aims to understand STY-restricting host factors typically evaded in human macrophages, allowing for future targeted drug development against this global pathogen. Further preliminary findings demonstrate that induction of the ISR by STY requires the ISR kinase GCN2, a sensor of nutrient stress and ribosomal dysfunction. I find that BMDMs lacking GCN2 produce lower levels of inflammatory cytokines and permit higher STY burden during infection than WT controls. Additional preliminary data suggest that GCN2 controls macrophage polarization and metabolic reprogramming in response to STY. Together, these data inform my hypothesis that S. Typhi activation of the macrophage ISR shapes the innate immune response and infection outcomes. To test this hypothesis, I will perform two aims that reveal the role of GCN2 in shaping macrophage metabolism and the macrophage functions impacted by ISR activation in response to STY. Using cell culture, metabolomics, and in vivo infection techniques, this proposal will capture how cellular stress defines the potential of a critical innate immune cell during STY infection. Discoveries made through completion of these aims will be significant as studies of S. Typhi infection biology have limited due to STY’s human-restricted host adaptation.