Covid-19: Fast-tracking treatment by exploiting the steroid hormone receptor/TMPRSS2 axis

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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.