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Principal Investigator: David Changli WEI
Organization: UNIVERSITY OF TEXAS MED BR GALVESTON
Fiscal Year: 2024
Award: $606,134
Funding agency: National Institute of Diabetes and Digestive and Kidney Diseases
Summary
Viral infection is a major contributor to the global burden of infectious diseases. Virus-related glomerular diseases
are seen in increasing frequency in clinical practice but are still underrecognized, thus miss opportunities for
timely treatment. Viral exposure can alter host immunity in subtle ways, leaving an indelible footprint on the
immune system. While there have been many studies indicating the association of viral infection with glomerular
disease, a direct involvement of virus in kidney barrier dysfunction is unknown in most cases. Among remarkable
research obstacles, lacking of a convenient and relevant animal model can be the most alarming one. We have
recently established a novel mouse model whereby viral proteins drive glomerular disease in concert with a
unique immune molecule, soluble urokinase receptor (suPAR). Intranasal injection of SARS-Cov-2 spike S1
protein (2019-nCov) caused proteinuria and podocyte injury specifically in mice with high levels of suPAR.
Treatment with anti-suPAR antibody in mice or anti- v 3 integrin antibody on human podocytes blocked
proteinuria and protected the glomerular filtration apparatus respectively. Notably, we found this unique synergy
between viral protein and host suPAR in causing glomerular disease applies to other integrin binding viruses as
well, including HIV-1 and Epstein-Barr virus (EBV). Clinically, suPAR is associated with kidney function loss in
patients with HIV-1 infection, and in those with moderate to severe Covid-19. Based on these intriguing new
insights, we hypothesize that viral-host suPAR interplay induces glomerular integrin activation and plays an
essential role in some virus-associated glomerular disease. We propose to test this hypothesis by
comprehensively evaluating the implication of viral protein-suPAR-integrin triad in both mouse models (Aim 1)
and virus-associated human glomerular diseases (Aim 2), utilizing state of the art tools, and unique combinations
of top-down and bottom-up approaches. Additionally, we will test therapeutic modalities targeting the vicious viral
protein-suPAR-integrin cycle with relevant small molecule inhibitors and antibodies (Aim 3).
Terms: <2019 novel corona virus><2019 novel coronavirus><2019-nCoV><2019-nCoV S protein><2019-nCoV spike glycoprotein><2019-nCoV spike protein><Affinity><Animal Model><Animal Models and Related Studies><Antibodies><Antigenic Determinants><B Cell Differentiation Factor I><B cell growth factor 2><B-Cell Growth Factor-II><BCGF-II><BCGF2><Binding><Binding Determinants><Burkitt Herpesvirus><Burkitt Lymphoma Virus><COVID crisis><COVID epidemic><COVID infected patient><COVID pandemic><COVID patient><COVID positive patient><COVID-19 S protein><COVID-19 crisis><COVID-19 epidemic><COVID-19 era><COVID-19 global health crisis><COVID-19 global pandemic><COVID-19 health crisis><COVID-19 infected patient><COVID-19 infection><COVID-19 pandemic><COVID-19 patient><COVID-19 period><COVID-19 positive patient><COVID-19 public health crisis><COVID-19 spike><COVID-19 spike glycoprotein><COVID-19 spike protein><COVID-19 virus><COVID-19 virus infection><COVID-19 years><COVID19 infection><COVID19 patient><COVID19 positive patient><COVID19 virus><Cell Attachment><Cell Body><Cell Communication and Signaling><Cell Signaling><Cell-Matrix Adhesions><Cell-Matrix Junction><Cells><Chronic Kidney Failure><Chronic Renal Disease><Chronic Renal Failure><Clinical><CoV-2><CoV2><Communicable Diseases><Coupled><Data><Devices><Disease><Disorder><Dysfunction><EB virus><EBV><Eo-CSF><Eosinophil Differentiation Factor><Epitopes><Epstein Barr Virus><Exposure to><Fc Receptor><Foot Process><Frequencies><Functional disorder><Glomerular Filtration Rate><Glomerular disease><HHV-4><HHV4><HIV Envelope Glycoprotein gp120><HIV Envelope Protein gp120><HIV env Protein gp120><HIV-1><HIV-I><HIV1><HTLV-III gp120><Hantavirus Infections><Hospital Admission><Hospitalization><Human><Human Herpesvirus 4><Human Immunodeficiency Virus Type 1><Human immunodeficiency virus 1><IL-5><IgA enhancing factor><Immune><Immune system><Immunes><Immunity><Impairment><In Vitro><Infection><Infectious Disease Pathway><Infectious Diseases><Infectious Disorder><Infectious Mononucleosis Virus><Influenza B><Influenza B Virus><Influenza Viruses Type B><Injections><Injury><Integrin Binding><Integrin Inhibition><Integrins><Integrins Extracellular Matrix><Interleukin 5 Precursor><Interleukin-5><Intracellular Communication and Signaling><Kidney><Kidney Diseases><Kidney Urinary System><Mice><Mice Mammals><Modality><Modeling><Modern Man><Molecular><Molecular Interaction><Monitor><Murine><Mus><NGS Method><NGS system><Nephropathy><Orthomyxoviruses Type B><Patients><Pedicel><Photometry><Physiopathology><Play><Proteins><Proteinuria><Publishing><Renal Disease><Renal Glomerular Diseases and Syndromes><Renal function><Renal glomerular disease><Renal glomerular disease or syndrome><Renal glomerular disorder><Renal glomerular syndrome><Research><Role><SARS corona virus 2><SARS-CO-V2><SARS-COVID-2><SARS-CoV-2><SARS-CoV-2 S><SARS-CoV-2 S protein><SARS-CoV-2 epidemic><SARS-CoV-2 global health crisis><SARS-CoV-2 global pandemic><SARS-CoV-2 infected patient><SARS-CoV-2 infection><SARS-CoV-2 pandemic><SARS-CoV-2 patient><SARS-CoV-2 positive patient><SARS-CoV-2 spike><SARS-CoV-2 spike glycoprotein><SARS-CoV-2 spike protein><SARS-CoV2><SARS-CoV2 infection><SARS-associated corona virus 2><SARS-associated coronavirus 2><SARS-coronavirus-2><SARS-coronavirus-2 epidemic><SARS-coronavirus-2 pandemic><SARS-related corona virus 2><SARS-related coronavirus 2><SARSCoV2><Scanning><Serology><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 CoV 2 epidemic><Severe Acute Respiratory Syndrome CoV 2 pandemic><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 coronavirus 2><Severe acute respiratory syndrome coronavirus 2 S protein><Severe acute respiratory syndrome coronavirus 2 epidemic><Severe acute respiratory syndrome coronavirus 2 infection><Severe acute respiratory syndrome coronavirus 2 pandemic><Severe acute respiratory syndrome coronavirus 2 spike glycoprotein><Severe acute respiratory syndrome coronavirus 2 spike protein><Severe acute respiratory syndrome related corona virus 2><Signal Transduction><Signal Transduction Systems><Signaling><T cell replacing factor><T-Cell Replacing Factor><Testing><Therapeutic><Therapeutic Intervention><U-PA receptor><Ultrafiltration><Urokinase Plasminogen Activator Receptor><Urokinase Receptor><Urokinase-type Plasminogen Activator Receptor><Viral><Viral Diseases><Viral Gene Products><Viral Gene Proteins><Viral Proteins><Virus><Virus Diseases><Visceral Epithelial Cell><Wuhan coronavirus><antibody receptor><biological signal transduction><burden of disease><burden of illness><chronic kidney disease><clinical practice><coronavirus disease 2019 S protein><coronavirus disease 2019 crisis><coronavirus disease 2019 epidemic><coronavirus disease 2019 global health crisis><coronavirus disease 2019 global pandemic><coronavirus disease 2019 health crisis><coronavirus disease 2019 infected patient><coronavirus disease 2019 infection><coronavirus disease 2019 pandemic><coronavirus disease 2019 patient><coronavirus disease 2019 positive patient><coronavirus disease 2019 public health crisis><coronavirus disease 2019 spike glycoprotein><coronavirus disease 2019 spike protein><coronavirus disease 2019 virus><coronavirus disease crisis><coronavirus disease epidemic><coronavirus disease infected patient><coronavirus disease pandemic><coronavirus disease patient><coronavirus disease positive patient><coronavirus disease-19 global pandemic><coronavirus disease-19 pandemic><coronavirus disease-19 patient><coronavirus disease-19 virus><coronavirus patient><damage to kidney><determine efficacy><disease burden><efficacy analysis><efficacy assessment><efficacy determination><efficacy evaluation><efficacy examination><evaluate efficacy><examine efficacy><glomerular filtration><glomerular visceral epithelial cell><gp120><gp120 ENV Glycoprotein><gp120(HIV)><hCoV19><in vivo><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><injuries><innovate><innovation><innovative><insight><integrin bound><intervention therapy><kidney damage><kidney disorder><kidney function><life-threatening COVID><life-threatening COVID-19><life-threatening SARS-CoV-2><life-threatening coronavirus disease><life-threatening coronavirus disease 2019><life-threatening severe acute respiratory syndrome coronavirus 2><loss of function><model of animal><mouse model><murine model><nCoV2><new drug target><new drug treatments><new druggable target><new drugs><new pharmacological therapeutic><new pharmacotherapy target><new therapeutic target><new therapeutics><new therapy><new therapy target><next gen sequencing><next generation sequencing><next generation therapeutics><nextgen sequencing><novel><novel drug target><novel drug treatments><novel druggable target><novel drugs><novel pharmaco-therapeutic><novel pharmacological therapeutic><novel pharmacotherapy target><novel therapeutic target><novel therapeutics><novel therapy><novel therapy target><overexpress><overexpression><pathophysiology><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><pro-urokinase receptor><renal><renal damage><renal disorder><scRNA-seq><serious COVID><serious COVID-19><serious SARS-CoV-2><serious coronavirus disease><serious coronavirus disease 2019><serious severe acute respiratory syndrome coronavirus 2><severe COVID><severe COVID-19><severe COVID19><severe SARS-CoV-2><severe acute respiratory syndrome coronavirus 2 global health crisis><severe acute respiratory syndrome coronavirus 2 global pandemic><severe acute respiratory syndrome coronavirus 2 infected patient><severe acute respiratory syndrome coronavirus 2 patient><severe acute respiratory syndrome coronavirus 2 positive patient><severe coronavirus disease><severe coronavirus disease 19><severe coronavirus disease 2019><severe severe acute respiratory syndrome coronavirus 2><single cell RNA-seq><single cell RNAseq><single cell expression profiling><single cell transcriptomic profiling><single-cell RNA sequencing><small molecular inhibitor><small molecule inhibitor><social role><spike proteins on SARS-CoV-2><synergism><therapeutic evaluation><therapeutic testing><tool><uPAR receptor><viral infection><virus infection><virus protein><virus-induced disease>