COVID-19 and Kidney Injury: Urinary Transcriptomics of Kidney Injury in Novel Nonhuman Primate Models of SARS-CoV-2

ABSTRACT/SUMMARY The severe acute respiratory syndrome coronavirus-2 (SARS CoV-2), etiologic agent of the COVID-19, is the cause of the current worldwide pandemic with unprecedented public health issues. The lung is the most severely injured organ by SARS-CoV-2, but the kidney appears to be damaged as well. In 90% of patients with COVID-19 on mechanical ventilation, acute kidney injury (AKI) occurs early, leading to poor prognosis and high in-hospital mortality. Angiotensin (Ang) converting ezyme-2 (ACE2), a member of the renin-angiotensin system, opposes Ang II actions and exerts beneficial CV effects. There is mounting evidence that ACE-2, acts as a major entry receptor for SARS-CoV-2. Because ACE2 is expressed in proximal tubules, podocytes, mesangial cells, parietal epithelium of Bowman's capsule and collecting ducts, it is critical to elucidate the effects of COVID-19 in the development of AKI. Animal models have been used extensively during previous outbreaks of SARS- CoV to model disease progression and to test vaccines and therapeutics. Non-human primates (NHPs) are ideally suited to model respiratory viral infections in humans primarily due to their similarities in anatomy and immunologic responses. Chad J. Roy, PhD (Director of Infectious Disease Aerobiology, Tulane National Primate Research Center, and Co-Investigator of this project) has recently generated novel and translational NHP models of COVID-19 using SARS-CoV-2 infection via nasal/intratracheal inoculation, which is able to reproduce the rapid clinical deterioration seen in people with severe COVID-19. In this pilot exploratory study, we propose to assess urine transcriptomics in two novel NHP (Rhesus macaque and African green) models of SARS-2-CoV-2 infection and their associations with early markers of AKI. Our overall hypothesis is that, because ACE2 may play a critical role in COVID-19-induced kidney injury, changes in urinary transcriptional signatures are associated with alterations of urinary early kidney injury markers and reflect the effects of SARS-CoV-2 on kidney ACE2-expressing cells and renal function. Using urine transcriptomics assessed by single-cell RNA-sequencing in ACE2-expressing cells isolated from urines collected during early infection, progression, and recovery phases of COVID-19, urinary measurements of kidney injury markers (EGF, MCP-1, NGAL), and clinical parameters of kidney function, we propose the following Specific aim: To test the hypothesis that the effects of SARS-CoV2 on the kidney are evidenced by changes of urine transcriptomics and accompanied by early excretion of kidney injury markers in NHPs with SARS-CoV-2 infection by mean of: A) To assess the temporal changes of urinary kidney injury markers during early infection, progression, and recovery phases of COVID-19. B) To determine whether urinary excretion of early kidney injury markers precede clinical parameters of kidney impairment and AKI; and C) To examine changes of urine transcriptomics in ACE2-expressing cells at a single-cell resolution during COVID-19. The success of the proposed study will help to elucidate the value of gene expression-based cell type enrichment analyses in urine as initial signals of renal injury during the progression of COVID-19.