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Principal Investigator: Kerry L Burnstein
Organization: MIAMI VA HEALTH CARE SYSTEM
Fiscal Year: 2023
Funding agency: Veterans Affairs
COVID-19 poses a tremendous health threat, particularly to individuals overrepresented in the US
Veteran community. COVID-19 mortality is greater in men than in women; while this disparity is at least
partially due to factors such as higher rates of smoking, a hormonal link is likely and can be rapidly tested
therapeutically by repurposing existing drugs. The viral etiologic agent of COVID-19, SARS-CoV-2 (CoV-2),
attaches to human airway epithelium via the viral spike (S) protein, which binds to angiotensin-converting
enzyme 2 (ACE2) on the host cell surface. Viral entry requires S protein cleavage by the serine protease
TMPRSS2, which is a known transcriptional target of the androgen receptor (AR). Lung epithelial cells (a target
of CoV-2 infection) express transcriptionally active AR. We hypothesize that AR up-regulates TMPRSS2 in
lung epithelial cells and thereby promotes viral entry and infectivity. We propose that FDA-approved
AR antagonists will decrease CoV-2 entry and spread and can be rapidly repurposed for COVID-19. IL-6
is the major cytokine released in moderate and severe COVID-19 cases and both published and our
preliminary data show that IL-6 enhances AR transcriptional activity. We will therefore also examine the
contribution of interleukin 6 (IL-6) to AR regulation of TMPRRS2. To facilitate these studies in a robust manner,
we propose to isolate the SARS-CoV-2 entry mechanism through the use of luciferase-expressing
pseudovirions that harbor the SARS-CoV-2 S protein. Such a reporter system has high reproducibility,
versatility and dynamic range, allowing for the rapid, accurate and specific assessment of a large range of viral
entry regulators into primary human lung epithelial cells and lung adenocarcinoma cell lines under BSL2+
conditions. We will test whether AR inhibition reduces TMPRSS2 and the requisite S protein processing
thereby decreasing CoV-2 entry into host lung epithelial cells. Subsequently, we will confirm results on a
subset of promising compounds using live SARS-Cov-2 in an approved BSL3 facility. Safe and effective AR
antagonists are FDA approved for prostate cancer and this study will provide rationale to repurpose these
drugs for use in clinical trials for COVID-19.
The glucocorticoid receptor (GR) shares a common DNA response element consensus sequence with
AR. Furthermore, GR upregulation of TMPRSS2 has been shown in advanced prostate cancer. Therefore, in
parallel, we will examine whether TMPRSS2 is regulated by glucocorticoids (cortisol) and blocked by a GR
antagonist in models of human lung epithelia. Patients taking corticosteroids (including the elderly and
individuals with diabetes, hypertension and chronic inflammatory disease) are at the highest risk of death from
COVID-19. The World Health Organization has provided interim guidance to avoid glucocorticoids in COVID-
19 patients with severe acute respiratory distress syndrome. Therefore, understanding GR regulation of
TMPRSS2 is also essential to repurposing the TMPRSS2-inhibitory FDA-approved agents for COVID-19. Our
aims are to: (1) Evaluate steroid hormone receptor (AR and GR) regulation of TMPRSS2 in human primary
airway and lung epithelial cells and lung adenocarcinoma cell line models and (2) Examine the capacity of
FDA-approved AR and GR antagonists to block CoV-2 entry and infectivity in human primary airway and lung
epithelial cells.
US Veterans represent several demographics acutely afflicted by COVID-19. Older US Veterans are
particularly vulnerable because of higher comorbidities including smoking, diabetes, heart disease and
hypertension. Burden on the Veteran community is also proportionally higher given the propensity for poor
outcome in men as compared to women following COVID-19 infection. Since the anti-androgen therapies to be
tested are FDA approved for prostate cancer treatment and have also been used safely in women with breast
cancer, our study has potential for immediate impact to all veterans.
Terms: <2019 novel corona virus><2019 novel coronavirus><2019-nCoV><2019-nCoV S protein><2019-nCoV spike glycoprotein><2019-nCoV spike protein><5 alpha-Dihydrotestosterone><5-alpha-DHT><ACE2><ARDS><Acute><Acute Respiratory Distress><Acute Respiratory Distress Syndrome><Address><Adrenal Cortex Hormones><Adult ARDS><Adult RDS><Adult Respiratory Distress Syndrome><Aeroseb-HC><Affect><Agonist><Androgen Antagonists><Androgen Receptor><Androstanolone><Anti-Androgen><Anti-Androgen Agents><Anti-androgen Therapy><Anti-androgen Treatment><Antiandrogen Agents><Antiandrogen Therapy><Antiandrogen Treatment><Antiandrogens><B cell differentiation factor><B cell stimulating factor 2><B-Cell Differentiation Factor><B-Cell Differentiation Factor-2><B-Cell Stimulatory Factor-2><BCDF><BSF-2><BSF2><BSL-3 facility><BSL3 facility><Binding><Breast Cancer><COVID infected patient><COVID patient><COVID positive patient><COVID-19><COVID-19 S protein><COVID-19 associated death><COVID-19 associated fatality><COVID-19 associated mortality><COVID-19 death><COVID-19 fatality><COVID-19 induced death><COVID-19 induced fatality><COVID-19 induced mortality><COVID-19 infected patient><COVID-19 infection><COVID-19 mortality><COVID-19 patient><COVID-19 positive patient><COVID-19 related death><COVID-19 related fatality><COVID-19 related mortality><COVID-19 spike glycoprotein><COVID-19 spike protein><COVID-19 therapy><COVID-19 treatment><COVID-19 virus><COVID-19 virus infection><COVID19><COVID19 S protein><COVID19 associated death><COVID19 associated fatality><COVID19 associated mortality><COVID19 death><COVID19 fatality><COVID19 induced death><COVID19 induced fatality><COVID19 induced mortality><COVID19 infection><COVID19 mortality><COVID19 patient><COVID19 positive patient><COVID19 related death><COVID19 related fatality><COVID19 related mortality><COVID19 spike glycoprotein><COVID19 spike protein><COVID19 therapy><COVID19 treatment><COVID19 virus><CV-19><CV19><Cardiac Diseases><Cardiac Disorders><Causality><Cell Line><Cell surface><CellLine><Cetacort><Clinical Trials><CoV-2><CoV2><Collaborations><Colorado><Communities><Consensus Sequence><Cort-Dome><Cortef><Cortenema><Corticoids><Corticosteroids><Cortisol><Cortispray><Cortril><DNA><Da Nang Lung><Data><Deoxyribonucleic Acid><Dermacort><Diabetes Mellitus><Dihydrotestosterone><Disease><Disorder><Disparities><Disparity><Drug usage><Drugs><Eldecort><Elderly><Enrollment><Epithelial Cells><Epitheliasin Gene><Epithelium><Etiology><FDA approved><Gene Transcription><Genetic Transcription><Glucocorticoid Receptor><Glucocorticoids><HPGF><Health><Health Care Providers><Health Personnel><Healthcare Providers><Healthcare worker><Heart Diseases><Hepatocyte-Stimulating Factor><Hormonal><Human><Hybridoma Growth Factor><Hydrocortisone><Hydrocortone><Hypertension><Hytone><IFN-beta 2><IFNB2><IL-6><IL6 Protein><Individual><Interdisciplinary Research><Interdisciplinary Study><Interleukin-6><Ligands><Link><Luciferase Immunologic><Luciferases><Lung><Lung Adenocarcinoma><Lung Respiratory System><MGI-2><Malignant Tumor of the Prostate><Malignant neoplasm of prostate><Malignant prostatic tumor><Measures><Medication><Modeling><Modern Man><Molecular Interaction><Multidisciplinary Collaboration><Multidisciplinary Research><Myeloid Differentiation-Inducing Protein><Nuclear Receptors><Nutracort><Outcome><PRSS10><Patients><Pattern><Pharmaceutic Preparations><Pharmaceutical Preparations><Pharmacological Treatment><Plasmacytoma Growth Factor><Proctocort><Prostate><Prostate CA><Prostate CA therapy><Prostate Cancer><Prostate Cancer therapy><Prostate Gland><Prostate malignancy><Prostatic Cancer><Prostatic Gland><Protein Cleavage><Proteins><Proteolysis><Publishing><RNA Expression><Receptor Inhibition><Receptor Up-Regulation><Regulation><Reporter><Reproducibility><Research><Resistance><Respiratory Epithelium><Response Elements><SARS corona virus 2><SARS-CO-V2><SARS-COVID-2><SARS-CoV-2><SARS-CoV-2 S protein><SARS-CoV-2 associated death><SARS-CoV-2 associated fatality><SARS-CoV-2 associated mortality><SARS-CoV-2 death><SARS-CoV-2 entry inhibitor><SARS-CoV-2 fatality><SARS-CoV-2 induced death><SARS-CoV-2 induced fatality><SARS-CoV-2 induced mortality><SARS-CoV-2 infected patient><SARS-CoV-2 infection><SARS-CoV-2 mortality><SARS-CoV-2 patient><SARS-CoV-2 positive patient><SARS-CoV-2 related death><SARS-CoV-2 related fatality><SARS-CoV-2 related mortality><SARS-CoV-2 spike glycoprotein><SARS-CoV-2 spike protein><SARS-CoV-2 therapy><SARS-CoV-2 treatment><SARS-CoV2><SARS-CoV2 S protein><SARS-CoV2 infection><SARS-CoV2 spike glycoprotein><SARS-CoV2 spike protein><SARS-associated corona virus 2><SARS-associated coronavirus 2><SARS-coronavirus-2><SARS-related corona virus 2><SARS-related coronavirus 2><SARSCoV2><Serine Endopeptidases><Serine Protease><Serine Protein Hydrolases><Serine Proteinases><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 coronavirus 2><Severe acute respiratory syndrome coronavirus 2 S protein><Severe acute respiratory syndrome coronavirus 2 entry inhibitor><Severe acute respiratory syndrome coronavirus 2 infection><Severe acute respiratory syndrome coronavirus 2 spike glycoprotein><Severe acute respiratory syndrome coronavirus 2 spike protein><Severe acute respiratory syndrome related corona virus 2><Shock Lung><Smoking><Stanolone><Stiff lung><Strains Cell Lines><Structure of respiratory epithelium><System><TMPRSS2><TMPRSS2 gene><Testing><Therapeutic><Therapeutic Androstanolone><Transcription><Universities><Vascular Hypertensive Disease><Vascular Hypertensive Disorder><Veterans><Viral><Virus><Woman><World Health Organization><Wuhan coronavirus><advanced age><advanced prostate cancer><after COVID-19 infection><after SARS-CoV-2 infection><after SARS-CoV2 infection><after infection by SARS-CoV-2><after severe acute respiratory distress syndrome CoV-2 infection><airway epithelium><androgen inhibitor><angiotensin converting enzyme 2><angiotensin converting enzyme II><antagonism><antagonist><biosafety level 3 facility><block SARS-CoV-2 entry><block severe acute respiratory syndrome coronavirus 2 entry><block viral entry><castrate resistant PCa><castrate resistant prostate cancer><castration resistant CaP><castration resistant PCa><castration resistant prostate cancer><causation><chronic inflammatory disease><co-morbid><co-morbidity><comorbidity><corona virus disease 2019><coronavirus disease 2019><coronavirus disease 2019 S protein><coronavirus disease 2019 associated death><coronavirus disease 2019 associated fatality><coronavirus disease 2019 associated mortality><coronavirus disease 2019 death><coronavirus disease 2019 fatality><coronavirus disease 2019 induced death><coronavirus disease 2019 induced fatality><coronavirus disease 2019 induced mortality><coronavirus disease 2019 infected patient><coronavirus disease 2019 infection><coronavirus disease 2019 mortality><coronavirus disease 2019 patient><coronavirus disease 2019 positive patient><coronavirus disease 2019 related death><coronavirus disease 2019 related fatality><coronavirus disease 2019 related mortality><coronavirus disease 2019 spike glycoprotein><coronavirus disease 2019 spike protein><coronavirus disease 2019 therapy><coronavirus disease 2019 treatment><coronavirus disease 2019 virus><coronavirus disease infected patient><coronavirus disease patient><coronavirus disease positive patient><coronavirus disease-19><coronavirus disease-19 mortality><coronavirus disease-19 patient><coronavirus disease-19 virus><coronavirus infectious disease-19><coronavirus patient><cultured cell line><cytokine><death due to COVID-19><death due to COVID19><death due to SARS-CoV-2><death due to coronavirus disease 2019><death due to severe acute respiratory syndrome coronavirus 2><death in COVID><death in COVID-19><death in SARS-CoV-2><death in coronavirus disease><death in coronavirus disease 2019><death in severe acute respiratory syndrome coronavirus 2><demographics><diabetes><disease causation><drug repurposing><drug use><drug/agent><elders><enroll><fatality due to COVID-19><fatality due to COVID19><fatality due to SARS-CoV-2><fatality due to coronavirus disease 2019><fatality due to severe acute respiratory syndrome coronavirus 2><following COVID-19 infection><following SARS-CoV-2 infection><following SARS-CoV2 infection><following infection by SARS-CoV-2><following severe acute respiratory distress syndrome CoV-2 infection><geriatric><global gene expression><global transcription profile><hCoV19><health care personnel><health care worker><health provider><health workforce><healthcare personnel><heart disorder><high blood pressure><high risk><human model><hyperpiesia><hyperpiesis><hypertensive disease><hypertensive disorder><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><inhibit SARS-CoV-2 entry><inhibit severe acute respiratory syndrome coronavirus 2 entry><inhibit viral entry><interferon beta 2><late life><later life><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><loved ones><mRNA Expression><male><malignant breast neoplasm><malignant breast tumor><medical personnel><men><model of human><mortality due to COVID-19><mortality due to COVID19><mortality due to SARS-CoV-2><mortality due to coronavirus disease 2019><mortality due to severe acute respiratory syndrome coronavirus 2><nCoV2><older adult><older person><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><post SARS-CoV-2 infection><previous COVID-19 infection><previous SARS-CoV-2 infection><previous SARS-CoV2 infection><previous severe acute respiratory distress syndrome CoV-2 infection><prior COVID-19 infection><prior SARS-CoV-2 infection><prior SARS-CoV2 infection><prior severe acute respiratory distress syndrome CoV-2 infection><prostate cancer treatment><protein expression><pulmonary><receptor upregulation><repurposing agent><repurposing medication><resistant><respiratory tract epithelium><response><senior citizen><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 associated death><severe acute respiratory syndrome coronavirus 2 associated fatality><severe acute respiratory syndrome coronavirus 2 associated mortality><severe acute respiratory syndrome coronavirus 2 death><severe acute respiratory syndrome coronavirus 2 fatality><severe acute respiratory syndrome coronavirus 2 induced death><severe acute respiratory syndrome coronavirus 2 induced fatality><severe acute respiratory syndrome coronavirus 2 induced mortality><severe acute respiratory syndrome coronavirus 2 infected patient><severe acute respiratory syndrome coronavirus 2 mortality><severe acute respiratory syndrome coronavirus 2 patient><severe acute respiratory syndrome coronavirus 2 positive patient><severe acute respiratory syndrome coronavirus 2 related death><severe acute respiratory syndrome coronavirus 2 related fatality><severe acute respiratory syndrome coronavirus 2 related mortality><severe acute respiratory syndrome coronavirus 2 therapy><severe acute respiratory syndrome coronavirus 2 treatment><severe coronavirus disease><severe coronavirus disease 19><severe coronavirus disease 2019><severe severe acute respiratory syndrome coronavirus 2><steroid hormone receptor><therapeutic evaluation><therapeutic testing><transcriptome><treat COVID-19><treat COVID19><treat SARS-CoV-2><treat coronavirus disease 2019><treat severe acute respiratory syndrome coronavirus 2><treatment provider><viral entry blocker><viral entry inhibitor><wet lung>