Identification of Host-Specific Determinants of APOL1-associated COVAN

ABSTRACT Coronavirus disease 2019 (COVID-19)-associated nephropathy (COVAN) is a severe form of kidney disease resulting from collapse of the glomerular tuft and manifesting clinically with proteinuria and high rates of kidney failure. More than 90% of COVAN cases are associated with two coding variants in the apolipoprotein L1 (APOL1) gene. These variants are mainly found in persons with Black, African American, or Hispanic ancestry. The objective of this proposal is to identify patient-specific determinants of APOL1-mediated COVAN penetrance. Our published and preliminary data suggest that: 1. APOL1 is robustly expressed in the glomeruli of patients with COVAN but not in healthy controls. 2. COVID-19-induced cytokines upregulate pathogenic APOL1 variants via JAK-STAT signaling in human kidney organoids and, in turn, cause podocyte injury. 3. Cytokine-induced podocyte injury is blocked by inhibition of JAK/STAT/APOL1 axis. 4. Expression of variant APOL1 protein is sufficient to cause dose-dependent cytotoxicity in vitro. Consistent with these discoveries, others found that expression of APOL1 variants caused glomerulosclerosis in transgenic mice. Based on these published and preliminary data, we hypothesize that maladaptive crosstalk between glomerular cells and immune cells drive increased expression of APOL1 and the pathogenesis of COVAN. Moreover, that patients who develop COVAN either express higher levels of pathogenic cytokines (those cytokines known to induce APOL1 expression), or the glomerular cells of these individuals have an enhanced and maladaptive response to the same level of cytokine. To test this hypothesis, we will leverage unique patient-derived kidney organoids and immune cells of persons with biopsy-proven COVAN (collected after patients have recovered from infection). We propose two aims: 1.) Delineate the divergent biological responses of kidney organoids derived from COVAN patients versus controls after (i) infection with SARS-CoV-2 or (ii) treatment with COVID-19 induced cytokines. 2.) Identify differences in cellular response of immune cells of COVAN patients versus controls after (i) infection with SARS-CoV2 or (ii) treatment with COVID-19 induced cytokines. Identifying host- factors that regulate APOL1 and immune-glomerular interactions in COVAN will provide novel biomarkers and therapeutic targets for modulating APOL1 expression to treat COVAN and other forms of APOL1 nephropathy, helping to mitigate disparities in kidney disease. Execution of these scientific aims and completion of the career development activities of this proposal, along with the experienced mentorship and strong institutional support, will prepare me for a career as an independent physician scientist equipped for research into APOL1- mediated, inflammatory-mediated, and viral-mediated nephropathies.