Identification of a Special Cell Type as a Determinant of the Kidney Tropism of SARS-CoV-2

Background: Coronavirus disease-2019 (COVID-19) is an infectious disease caused by a novel discovered coronavirus, the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). The kidney tropism of SARS-CoV-2 has been well-validated clinically and often leads to various forms of renal damage in COVID-19 patients. However, the underlying mechanisms and diagnostic approaches remain to be determined. Methods: We interrogated the expression of virus-related host factors in singlecell RNA sequencing (scRNA-seq) datasets of normal human kidneys and kidneys with pre-existing diseases. We validated the results with immunohistochemistry and urinary proteomics of COVID-19 patients and healthy individuals. We also assessed the effects of genetic variants on kidney susceptibility using expression quantitative trait loci (eQTLs) databases. Results: We identified a subtype of renal tubular cells, which we named PT-3 cells, as being vulnerable to SARS-COV-2 infections in the kidneys. PT-3 cells were enriched in viral entry factors and replication and assembly machinery, but lacked antiviral restriction factors. PT-3 demonstrated higher proportion of ACE2+/CTSB+ double positive cells compared with other PTECs (20.54% vs 2.24%). Immunohistochemistry confirmed positive staining of PT-3 cells marker SCL36A2 (according to single cell RNA-seq datasets) on kidney sections from COVID-19 patients and healthy individuals. Urinary proteomics confirmed that the protein levels of PT-3 markers, in addition to ACE2, CTSB, and restriction factors, were significantly increased in the urine of COVID-19 patients. We further found that the proportion of PT-3 cells increased in diabetic nephropathy but decreased in kidney allografts and lupus nephropathy, suggesting that kidney susceptibility varied among these diseases. We finally identified several eQTLs that regulate the expression of host factors in kidney cells. Conclusions: We comprehensively characterized the expression patterns and expression levels of viral host factors in human kidney cells and identified PT-3 cells, a special subtype of PTECs that facilitates the SARS-CoV-2 invasion of the kidney. The detection of PT-3 cells markers in human urine may be used to assess the risk of renal infection during COVID-19.