Document text
Principal Investigator: Maria Blasi
Organization: DUKE UNIVERSITY
Fiscal Year: 2022
Award: $402,500
Funding agency: National Institute of Diabetes and Digestive and Kidney Diseases
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.
Terms: <2019 novel corona virus><2019 novel coronavirus><2019-nCoV><2019-nCoV variant><2019-nCoV variant forms><2019-nCoV variant strains><AIDS Virus><Acquired Immune Deficiency Syndrome Virus><Acquired Immunodeficiency Syndrome Virus><Acute Kidney Tubular Necrosis><Acute Renal Failure with Renal Papillary Necrosis><Acute Renal Failure with Tubular Necrosis><Affect><African Green Monkey><Archives><Assay><Autopsy><Bioassay><Biologic Assays><Biological Assay><Biopsy><Body Tissues><COVID infected patient><COVID patient><COVID positive patient><COVID-19><COVID-19 genome><COVID-19 infected patient><COVID-19 infection><COVID-19 patient><COVID-19 positive patient><COVID-19 therapy><COVID-19 treatment><COVID-19 variant><COVID-19 variant forms><COVID-19 variant strains><COVID-19 virus><COVID-19 virus genome><COVID19><COVID19 genome><COVID19 infection><COVID19 patient><COVID19 positive patient><COVID19 therapy><COVID19 treatment><COVID19 virus><COVID19 virus genome><CV-19><CV19><Cell Body><Cell Death><Cell Line><CellLine><Cells><Cessation of life><Chlorocebus aethiops><Chlorocebus sabaeus><Clotting><CoV-2><CoV2><Coagulation><Coagulation Process><Complication><DNA Alteration><DNA Sequence Alteration><DNA mutation><Data><Death><Deletion Mutation><Deposit><Deposition><Detection><Diagnosis><Disease><Disorder><Epithelial Cells><Frequencies><Generalized Growth><Genes><Genetic Alteration><Genetic Change><Genetic analyses><Genetic defect><Genetic mutation><Genome><Glomerular disease><Goals><Green Monkey><Growth><HIV><Hospital Mortality><Human Immunodeficiency Viruses><In Vitro><In-house Mortalities><Infection><Inflammation><Inflammatory><Inflammatory Response><Inhospital Mortality><Injury><Injury to Kidney><Kidney><Kidney Diseases><Kidney Tubules><Kidney Urinary System><LAV-HTLV-III><Lower Nephron Nephrosis><Lymphadenopathy-Associated Virus><Mechanical ventilation><Mitochondria><Morbidity><Morbidity - disease rate><Mutation><Nature><Nephropathy><Organ System><Pathogenesis><Patients><Pattern><Play><Prevalence><Pulmonary Body System><Pulmonary Organ System><Quantitative RTPCR><Quantitative Reverse Transcriptase PCR><Renal Cell><Renal Disease><Renal Glomerular Diseases and Syndromes><Renal glomerular disease><Renal glomerular disease or syndrome><Renal glomerular disorder><Renal glomerular syndrome><Renal tubule structure><Reporting><Research Resources><Research Specimen><Resources><Respiratory System><Respiratory Tracts><Respiratory tract structure><Role><SARS corona virus 2><SARS-CO-V2><SARS-COVID-2><SARS-CoV-2><SARS-CoV-2 genome><SARS-CoV-2 infected patient><SARS-CoV-2 infection><SARS-CoV-2 patient><SARS-CoV-2 positive patient><SARS-CoV-2 therapy><SARS-CoV-2 treatment><SARS-CoV-2 variant><SARS-CoV-2 variant forms><SARS-CoV-2 variant strains><SARS-CoV2><SARS-CoV2 genome><SARS-CoV2 infection><SARS-associated corona virus 2><SARS-associated coronavirus 2><SARS-coronavirus-2><SARS-related corona virus 2><SARS-related coronavirus 2><SARSCoV2><Sampling><Sequence Alteration><Severe Acute Respiratory Coronavirus 2><Severe Acute Respiratory Distress Syndrome CoV 2><Severe Acute Respiratory Distress Syndrome Corona Virus 2><Severe Acute Respiratory Distress Syndrome Coronavirus 2><Severe Acute Respiratory Syndrome CoV 2><Severe Acute Respiratory Syndrome-associated coronavirus 2><Severe Acute Respiratory Syndrome-related coronavirus 2><Severe acute respiratory syndrome associated corona virus 2><Severe acute respiratory syndrome corona virus 2><Severe acute respiratory syndrome coronavirus 2><Severe acute respiratory syndrome coronavirus 2 infection><Severe acute respiratory syndrome related corona virus 2><Site><Source><Specimen><Strains Cell Lines><Tissue Growth><Tissues><Urine><Urine Urinary System><Viral><Viral Diseases><Viral Pathogenesis><Viral Shedding><Virus><Virus Diseases><Virus Replication><Virus Shedding><Virus-HIV><Visceral Epithelial Cell><Wuhan coronavirus><acute kidney injury><acute tubular necrosis><adverse consequence><adverse outcome><body system><corona virus disease 2019><coronavirus disease 2019><coronavirus disease 2019 genome><coronavirus disease 2019 infected patient><coronavirus disease 2019 infection><coronavirus disease 2019 patient><coronavirus disease 2019 positive patient><coronavirus disease 2019 therapy><coronavirus disease 2019 treatment><coronavirus disease 2019 variant><coronavirus disease 2019 variant forms><coronavirus disease 2019 variant strains><coronavirus disease 2019 virus><coronavirus disease 2019 virus genome><coronavirus disease infected patient><coronavirus disease patient><coronavirus disease positive patient><coronavirus disease-19><coronavirus disease-19 patient><coronavirus disease-19 virus><coronavirus infectious disease-19><coronavirus patient><cultured cell line><cytokine><design><designing><genetic analysis><genome mutation><genomic alteration><glomerular visceral epithelial cell><hCoV19><hemodynamics><improved><infected with COVID-19><infected with COVID19><infected with SARS-CoV-2><infected with SARS-CoV2><infected with coronavirus disease 2019><infected with severe acute respiratory syndrome coronavirus 2><inflammation marker><inflammatory environment><inflammatory marker><inflammatory milieu><injuries><insight><intervention design><kidney cell><kidney disorder><kidney infection><kidney injury><mechanical respiratory assist><mechanically ventilated><mitochondrial><mutant><nCoV2><nasal swab><necrocytosis><necropsy><ontogeny><pandemic><pandemic disease><particle><patient infected with COVID><patient infected with COVID-19><patient infected with SARS-CoV-2><patient infected with coronavirus disease><patient infected with coronavirus disease 2019><patient infected with severe acute respiratory syndrome coronavirus 2><patient with COVID><patient with COVID-19><patient with COVID19><patient with SARS-CoV-2><patient with coronavirus disease><patient with coronavirus disease 2019><patient with severe acute respiratory distress syndrome coronavirus 2><podocyte><postmortem><prevent><preventing><prospective><public data base><public database><publicly accessible data base><publicly accessible database><publicly available data base><publicly available database><qRTPCR><renal><renal disorder><renal epithelium><renal injury><renal tubule><severe acute respiratory syndrome coronavirus 2 genome><severe acute respiratory syndrome coronavirus 2 infected patient><severe acute respiratory syndrome coronavirus 2 patient><severe acute respiratory syndrome coronavirus 2 positive patient><severe acute respiratory syndrome coronavirus 2 therapy><severe acute respiratory syndrome coronavirus 2 treatment><severe acute respiratory syndrome coronavirus 2 variant><severe acute respiratory syndrome coronavirus 2 variant forms><severe acute respiratory syndrome coronavirus 2 variant strains><shared data base><shared database><social role><systemic inflammation><systemic inflammatory response><therapy design><treat COVID-19><treat COVID19><treat SARS-CoV-2><treat coronavirus disease 2019><treat severe acute respiratory syndrome coronavirus 2><treatment design><viral RNA><viral fitness><viral infection><viral multiplication><viral replication><virus RNA><virus infection><virus multiplication><virus pathogenesis><virus-induced disease>