Understanding the interplay between local viral infection and local inflammation in COVID-19 kidney injury

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PROJECT ABSTRACT Acute kidney injury (AKI) is a common complication of Coronavirus disease 19 (COVID-19), affecting more than a third of patients hospitalized with COVID-19 and up to 90% of those requiring mechanical ventilation. Possible contributors to AKI in patients with COVID-19 include systemic inflammation and cytokine release, hemodynamic compromise, and intravascular coagulation. Additionally, several reports have suggested the presence of SARS- CoV-2 viral particles or viral RNA in the kidney tissue of patients who died from COVID-19, suggesting a potential role for local viral infection in the kidney. SARS-CoV-2 is known to infect and replicate in kidney cell lines, and in preliminary data we show that viral RNA can be amplified from the urine of patients with severe COVID-19 and AKI, even after the virus has been cleared in the respiratory tract. Genetic analysis of those viral RNA in urine demonstrated a predominant pattern of deletions and mutations at the furin-cleavage site of SARS-CoV-2 that have not been observed in over 180,000 SARS-CoV-2 genome sequences from respiratory tract samples deposited in the publicly available database GISAID. However, those mutations have been reported to occur after virus passaging in the African green monkey kidney cell line Vero-E6, raising the possibility that those mutations might be positively selected following virus replication in kidney cells. The primary goal of this application is to understand the interplay between local viral infection and local inflammation in COVID-19-related kidney injury by leveraging our expertise in the study of HIV-related kidney disease. Our specific objectives are 1) to isolate and genetically characterize SARS-CoV-2 from urine samples of COVID-19 patients with mild, moderate or severe disease, 2) to explore the relationship between SARS-CoV- 2 infection of renal cells and urine inflammatory markers; and 3) to determine the impact of genetic mutations on viral fitness. Understanding the role of direct viral infection of renal epithelial cells is key to the design of interventions to prevent and treat AKI in COVID-19. Further characterization of the viral mutants isolated from urine may provide insight into viral pathogenesis and would inform the design of antiviral and adjunctive therapies for SARS-CoV-2 infection.