Abstract It is well known in clinics that survivors of severe trauma and hemorrhagic shock (T/HS) face a significant risk of developing sepsis from infections, which causes high mortality. However, as the mechanisms of T/HS- predisposed infection remain unclear, few specific targets linking T/HS to elevated risk of sepsis have been identified. This proposal aims to address this important clinical problem by elucidating a previously unknown mechanism of T/HS regulation of immunometabolism that predisposes patients to infection. Here, we focus on the formation of a positive feedback loop for 12(S)-HETE-ALOX15, which is an unusual mechanism for the metabolite,12(S)-HETE, to upregulate the expression of its rate-limiting enzyme ALOX15. Emerging studies have demonstrated the important role of fatty acids (FAs) in the regulation of inflammation. A previous study identified plasma 12(S)-hydroxyeicosatetraenoic acid [12(S)-HETE] as a biomarker predicting trauma patient mortality, where 12(S)-HETE levels in non-surviving patients with severe trauma are 5-time higher than those in trauma survivors at the time of hospital admission. 12(S)-HETE is a metabolite from arachidonic acid (AA) generated by lipoxygenases. ALOX15, a lipoxygenase, is the rate- limiting enzyme in generating 12(S)-HETE. In our preliminary studies, we observed that 1) 12(S)-HETE increased host susceptibility to infection following T/HS; 2) 12(S)-HETE induces enhanced ALOX15 expression in macrophages (MPs), which forms a positive feedback loop that leads to enhanced generation of 12(S)-HETE, augmented MP death, and decreased bacteria clearance; and 3) blocking the feedback loop by genetic deletion of 12(S)-HETE receptor GPR31 or suppression of ALOX15 increased the bacteria clearance ability in the lungs and improved the survival rate following post-T/HS infection. Based on these findings, we hypothesize that the 12(S)-HETE-induced ALOX15 expression forms a positive feedback loop and serves as a novel mechanism underlying T/HS-predisposed sepsis. Blocking the feedback loop by ALOX15 inhibitor may present a therapeutic and preventive strategy for T/HS-predisposed sepsis. We propose two specific aims to test this hypothesis: Aim 1 is to determine the mechanism of 12(S)- HETE upregulation of ALOX15 expression in T/HS; and Aim 2 is to determine the role of 12(S)-HETE- ALOX15 feedback loop in the mechanism of T/HS-predisposed sepsis. To our knowledge, this study is the first attempt to evaluate the role of the T/HS-induced 12(S)-HETE- ALOX15 feedback loop in infection and sepsis susceptibility. We reason that the metabolite-enzyme feedback loop may represent an unexplored mechanism of T/HS-primed infection. Understanding this mechanism may provide a novel therapeutic target for the prevention and treatment of post-T/HS sepsis.