Each year, at least 1.7 million adults in the US develop sepsis and nearly 270,000 Americans die of sepsis. 1 in 3 patients who dies in a hospital has sepsis. African Americans have a 67% higher severe sepsis hospitalization rate and 20% more likely to die of sepsis compared to whites even after adjusting for co-variates. Close to 45% African American carry at least one APOL1 risk allele. Variants in APOL1 are thought to have arisen as a result of positive genetic selection, as they confer resistance against Trypanosome brucei rhodesiense, a parasite that causes African sleeping sickness. While having one risk variant imparts this crucial resistance against sleeping sickness, having two risk alleles significantly increases the risk of developing kidney disease. Recent genetic and mouse model studies indicate that APOL1 risk variant (RV) in endothelial cells might explain the increased sepsis susceptibility and severity in African Americans. Aim1. Define the role of RV APOL1 in sepsis in mouse models and patients. A. Characterize sepsis severity in mice with conditional inducible expression of RV and reference APOL1 in endothelial cells, kidney and liver cells. B. Examine the association between APOL1 RV genotype and sepsis incidence and severity in the Upenn (PMBB) and Vanderbilt (BioVU) Biobanks. C. Determine the association of plasma APOL1 level and sepsis severity in the MESSI cohort. Aim2. Define endothelial RV APOL1 induced pathology. A. Characterize RVAPOL1 endotheliopathy such as inflammation, permeability and coagulation changes using isogenic gene edited RV APOL1 human and mouse transgenic endothelial cells. B. Using single cell gene expression characterize changes associated with RV APOL1-induced endotheliopathy in vivo. C. Describe the cellular trafficking defect induced by RV APOL1 such as endocytosis, autophagy, and mitophagy in EC. Aim3. Determine whether pharmacological, or cell type specific genetic targeting of the inflammasome (NLRP3) and nucleotide sensing pathways (STING) alleviate endothelial RV APOL1 associated endotheliopathy and sepsis RV APOL1 is a critical determinant of health disparities affecting millions of people in the US. Our study will define the role endothelial of RV APOL1 in sepsis and could identify novel drugs to target RV APOL1

African Americans are 20% more likely to die of sepsis compared to people of European descent, even after adjusting for co-variates. Close to 45% African American carry at least one APOL1 risk allele, which has shown to be associated with increased incidence and severity of sepsis.