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1.
Life Sci Alliance ; 5(4)2022 04.
Article in English | MEDLINE | ID: covidwho-1675572

ABSTRACT

BACKGROUND: There are limited effective prophylactic/early treatments for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection. Viral entry requires spike protein binding to the angiotensin-converting enzyme-2 receptor and cleavage by transmembrane serine protease 2 (TMPRSS2), a cell surface serine protease. Targeting of TMPRSS2 by either androgen blockade or direct inhibition is in clinical trials in early SARS-CoV-2 infection. METHODS: We used differentiated primary human airway epithelial cells at the air-liquid interface to test the impact of targeting TMPRSS2 on the prevention of SARS-CoV-2 infection. RESULTS: We first modelled the systemic delivery of compounds. Enzalutamide, an oral androgen receptor antagonist, had no impact on SARS-CoV-2 infection. By contrast, camostat mesylate, an orally available serine protease inhibitor, blocked SARS-CoV-2 entry. However, oral camostat is rapidly metabolised in the circulation, with poor airway bioavailability. We therefore modelled local airway administration by applying camostat to the apical surface of differentiated airway cultures. We demonstrated that a brief exposure to topical camostat effectively restricts SARS-CoV-2 infection. CONCLUSION: These experiments demonstrate a potential therapeutic role for topical camostat for pre- or post-exposure prophylaxis of SARS-CoV-2, which can now be evaluated in a clinical trial.


Subject(s)
Respiratory Mucosa/drug effects , Respiratory Mucosa/metabolism , Respiratory Mucosa/virology , SARS-CoV-2/drug effects , SARS-CoV-2/physiology , Serine Endopeptidases/metabolism , Serine Proteinase Inhibitors/administration & dosage , Administration, Topical , Androgens/metabolism , Angiotensin-Converting Enzyme 2/genetics , Angiotensin-Converting Enzyme 2/metabolism , Antiviral Agents/pharmacology , COVID-19/prevention & control , COVID-19/virology , Cells, Cultured , Epithelial Cells , Esters/pharmacology , Gene Expression , Goblet Cells/immunology , Goblet Cells/metabolism , Guanidines/pharmacology , Host-Pathogen Interactions/drug effects , Humans , Serine Endopeptidases/genetics , Signal Transduction , Virus Internalization/drug effects , Virus Replication/drug effects
2.
Front Endocrinol (Lausanne) ; 12: 726696, 2021.
Article in English | MEDLINE | ID: covidwho-1581362

ABSTRACT

Epidemiological evidence shows clear gender disparities in the Coronavirus 2019 Disease (COVID-19) severity and fatality. This may reflect the contribution of gender-related factors, such as sex hormones, to COVID-19 pathogenesis. However, the mechanism linking gender disparities to COVID-19 severity is still poorly understood. In this review, we will pinpoint several elements involved in COVID-19 pathogenesis that are regulated by the two main sex hormones, estrogen and androgen. These include tissue specific gene regulation of SARS-CoV2 entry factors, innate and adaptive immune responses to infection, immunometabolism, and susceptibility to tissue injury by cytopathic effect or hyper-inflammatory response. We will discuss the mechanistic link between sex hormone regulation of COVID-19 pathogenetic factors and disease severity. Finally, we will summarize current evidence from clinical studies and trials targeting sex hormones and their signalling in COVID-19. A better understanding of the role of sex hormones in COVID-19 may identify targets for therapeutic intervention and allow optimization of treatment outcomes towards gender-based personalised medicine.


Subject(s)
Androgens/immunology , COVID-19/immunology , Estrogens/immunology , SARS-CoV-2/immunology , Androgens/metabolism , Angiotensin-Converting Enzyme 2/immunology , Angiotensin-Converting Enzyme 2/metabolism , COVID-19/metabolism , COVID-19/virology , Estrogens/metabolism , Female , Humans , Male , SARS-CoV-2/metabolism , SARS-CoV-2/physiology , Sex Factors , Virus Internalization
3.
Am J Physiol Renal Physiol ; 320(2): F243-F248, 2021 02 01.
Article in English | MEDLINE | ID: covidwho-1035216

ABSTRACT

Coronavirus disease 2019 (COVID-19) has reached pandemic proportions, affecting millions of people worldwide. Severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) is the causative agent of COVID-19. Epidemiological reports have shown that the severity of SARS-CoV-2 infection is associated with preexisting comorbidities such as hypertension, diabetes mellitus, cardiovascular diseases, and chronic kidney diseases, all of which are also risk factors for acute kidney injury (AKI). The kidney has emerged as a key organ affected by SARS-CoV-2. AKI is associated with increased morbidity and mortality in patients with COVID-19. Male sex is an independent predictor for AKI, and an increased death rate has been reported in male patients with COVID-19 worldwide. The mechanism(s) that mediate the sex discrepancy in mortality due to COVID-19 remain(s) unknown. Angiotensin-converting enzyme (ACE)2 is the receptor for SARS-CoV-2. Alterations in the ACE-to-ACE2 ratio have been implicated in renal diseases. This perspective aims to discuss data that suggest that androgens, via alterations in the intrarenal renin-angiotensin system, impair renal hemodynamics, predisposing patients to AKI during COVID-19 infection, which could explain the higher mortality observed in men with COVID-19. Clinicians should ensure early and effective cardiometabolic control for all patients to ameliorate the compensatory elevation of ACE2 and alterations in the ACE-to-ACE2 ratio. A better understanding of the role of androgens in SARS-CoV-2-associated AKI and mortality is imperative. The kidney could constitute a key organ that may explain the sex disparities of the higher mortality and worst outcomes associated with COVID-19 in men.


Subject(s)
Acute Kidney Injury/virology , Androgens/metabolism , COVID-19/mortality , COVID-19/pathology , Kidney/metabolism , SARS-CoV-2 , Acute Kidney Injury/metabolism , Acute Kidney Injury/pathology , Angiotensin-Converting Enzyme 2/metabolism , Female , Gene Expression Regulation , Humans , Male , Polycystic Ovary Syndrome , Renin-Angiotensin System/drug effects , Renin-Angiotensin System/physiology , Sex Factors , Transgender Persons
4.
Am J Physiol Heart Circ Physiol ; 320(1): H296-H304, 2021 01 01.
Article in English | MEDLINE | ID: covidwho-961166

ABSTRACT

Biological sex is increasingly recognized as a critical determinant of health and disease, particularly relevant to the topical COVID-19 pandemic caused by the SARS-CoV-2 coronavirus. Epidemiological data and observational reports from both the original SARS epidemic and the most recent COVID-19 pandemic have a common feature: males are more likely to exhibit enhanced disease severity and mortality than females. Sex differences in cardiovascular disease and COVID-19 share mechanistic foundations, namely, the involvement of both the innate immune system and the canonical renin-angiotensin system (RAS). Immunological differences suggest that females mount a rapid and aggressive innate immune response, and the attenuated antiviral response in males may confer enhanced susceptibility to severe disease. Furthermore, the angiotensin-converting enzyme 2 (ACE2) is involved in disease pathogenesis in cardiovascular disease and COVID-19, either to serve as a protective mechanism by deactivating the RAS or as the receptor for viral entry, respectively. Loss of membrane ACE2 and a corresponding increase in plasma ACE2 are associated with worsened cardiovascular disease outcomes, a mechanism attributed to a disintegrin and metalloproteinase (ADAM17). SARS-CoV-2 infection also leads to ADAM17 activation, a positive feedback cycle that exacerbates ACE2 loss. Therefore, the relationship between cardiovascular disease and COVID-19 is critically dependent on the loss of membrane ACE2 by ADAM17-mediated proteolytic cleavage. This article explores potential mechanisms involved in COVID-19 that may contribute to sex-specific susceptibility focusing on the innate immune system and the RAS, namely, genetics and sex hormones. Finally, we highlight here the added challenges of gender in the COVID-19 pandemic.


Subject(s)
Adaptive Immunity/immunology , Androgens/immunology , Angiotensin-Converting Enzyme 2/genetics , COVID-19/immunology , Estrogens/immunology , Immunity, Innate/immunology , Receptors, Coronavirus/genetics , ADAM17 Protein/metabolism , Adaptive Immunity/genetics , Androgens/metabolism , Angiotensin-Converting Enzyme 2/metabolism , COVID-19/genetics , COVID-19/metabolism , COVID-19/mortality , Cardiovascular Diseases/genetics , Cardiovascular Diseases/immunology , Estrogens/metabolism , Female , Genes, X-Linked/genetics , Genes, X-Linked/immunology , Humans , Immunity, Innate/genetics , Male , Promoter Regions, Genetic , Receptors, Coronavirus/metabolism , Renin-Angiotensin System/genetics , Renin-Angiotensin System/immunology , Response Elements/genetics , SARS-CoV-2/metabolism , Severity of Illness Index , Sex Characteristics , Sex Factors , X Chromosome Inactivation
5.
Endocr Relat Cancer ; 28(2): R47-R53, 2021 02.
Article in English | MEDLINE | ID: covidwho-953681

ABSTRACT

Androgens play a fundamental role in the morbidity and mortality of COVID-19, inducing both the ACE-2 receptor to which SARS-CoV-2 binds to gain entry into the cell, and TMPRS22, the transmembrane protease that primes the viral spike protein for efficient infection. The United States stands alone among developed nations in permitting one androgen, oral DHEA, to be freely available OTC and online as a 'dietary supplement'. DHEA is widely used by males in the US to offset the age-related decline in circulating androgens. This fact may contribute to the disparate statistics of COVID-19 morbidity and mortality in this country. In regulatory antithesis, every other developed nation regulates DHEA as a controlled substance. DHEA is an extremely potent inhibitor of glucose-6-phosphate dehydrogenase (G6PD), with uniquely unstable uncompetitive inhibition kinetics. This has particular relevance to COVID-19 because G6PD-deficient human cells have been demonstrated to be exceptionally sensitive to infection by human coronavirus. Because DHEA is lipophilic and freely passes into cells, oral DHEA bypasses the normal controls regulating androgen biology and uncompetitive G6PD inhibition. DHEA's status as a 'dietary supplement' means that no clinical trials demonstrating safety have been performed, and, in the absence of physician supervision, no data on adverse events have been collected. During the current pandemic, the unrestricted availability of oral DHEA as a 'dietary supplement' cannot be considered safe without proof from placebo-controlled clinical trials that it is not contributing to the severity of COVID-19. US physicians may therefore wish to query their patients' use of DHEA.


Subject(s)
COVID-19/metabolism , Dehydroepiandrosterone/adverse effects , Nonprescription Drugs/adverse effects , Androgens/metabolism , Animals , COVID-19/mortality , Dehydroepiandrosterone/administration & dosage , Female , Humans , Male , Nonprescription Drugs/administration & dosage , SARS-CoV-2/isolation & purification , Survival Rate , United States/epidemiology
6.
Cell Stem Cell ; 27(6): 876-889.e12, 2020 12 03.
Article in English | MEDLINE | ID: covidwho-927293

ABSTRACT

SARS-CoV-2 infection has led to a global health crisis, and yet our understanding of the disease and potential treatment options remains limited. The infection occurs through binding of the virus with angiotensin converting enzyme 2 (ACE2) on the cell membrane. Here, we established a screening strategy to identify drugs that reduce ACE2 levels in human embryonic stem cell (hESC)-derived cardiac cells and lung organoids. Target analysis of hit compounds revealed androgen signaling as a key modulator of ACE2 levels. Treatment with antiandrogenic drugs reduced ACE2 expression and protected hESC-derived lung organoids against SARS-CoV-2 infection. Finally, clinical data on COVID-19 patients demonstrated that prostate diseases, which are linked to elevated androgen, are significant risk factors and that genetic variants that increase androgen levels are associated with higher disease severity. These findings offer insights on the mechanism of disproportionate disease susceptibility in men and identify antiandrogenic drugs as candidate therapeutics for COVID-19.


Subject(s)
Androgens/metabolism , Angiotensin-Converting Enzyme 2/metabolism , COVID-19/metabolism , Patient Acuity , Receptors, Coronavirus/metabolism , Signal Transduction , Adult , Androgen Antagonists , Androgens/therapeutic use , Angiotensin-Converting Enzyme Inhibitors/therapeutic use , Animals , Antiviral Agents/therapeutic use , COVID-19/complications , COVID-19/drug therapy , Cells, Cultured , Chlorocebus aethiops , Drug Evaluation, Preclinical , Female , Humans , Male , Myocytes, Cardiac/drug effects , Myocytes, Cardiac/metabolism , Organoids/drug effects , Organoids/virology , Risk Factors , Sex Factors , Vero Cells
8.
IUBMB Life ; 72(12): 2533-2545, 2020 12.
Article in English | MEDLINE | ID: covidwho-836853

ABSTRACT

Novel SARS-CoV-2 named due to its close homology with severe acute respiratory syndrome coronavirus (SARS-CoV) is the etiologic agent for the ongoing pandemic outbreak causing loss of life and severe economic burden globally. The virus is believed to be evolved in a recombined form of bat and animal coronavirus with the capacity to infect human host using the ACE2 receptors as an entry point. Though the disease pathogenesis is not elucidated completely, the virus-mediated host response retains a similar pattern to that of previous SARS-CoV. Based on the available trend it is assumed that pediatric groups are less susceptible to the coronavirus. Understanding the possible mechanism that protects the children from hyper-inflammatory or disease severity could lead to better treatment modalities. In the present review, we have discussed the significance of age and sex-dependent pattern of ACE2 receptor expression and ACE2 variants in the immune protective mechanism of the disease virulence. We have also added a brief note on the importance of sex hormones in the pathogenesis of ACE2 mediated SARS-CoV2 infection.


Subject(s)
Angiotensin-Converting Enzyme 2/metabolism , COVID-19/etiology , Host-Pathogen Interactions , SARS-CoV-2/pathogenicity , Androgens/metabolism , Angiotensin-Converting Enzyme 2/genetics , Animals , COVID-19/epidemiology , Child , Cost of Illness , Estrogens/metabolism , Female , Humans , Male , Pandemics , Polymorphism, Genetic , Serine Endopeptidases/genetics , Virulence , Virus Diseases/epidemiology
9.
Trends Endocrinol Metab ; 31(12): 918-927, 2020 12.
Article in English | MEDLINE | ID: covidwho-791591

ABSTRACT

The recent coronavirus disease 2019 (COVID-19) pandemic showed a different severity in the disease between males and females. Men have been becoming severely ill at a higher rate than women. These data along with an age-dependent disease susceptibility and mortality in the elderly suggest that sex hormones are the main factors in determining the clinical course of the infection. The differences in aging males versus females and the role of sex hormones in key phenotypes of COVID-19 infection are described in this review. Recommendations based on a dimorphic approach for males and females suggest a sex-specific management the disease.


Subject(s)
Androgens/metabolism , COVID-19/mortality , Estrogens/metabolism , Sex Factors , Age Factors , Androgens/immunology , Angiotensin-Converting Enzyme 2/metabolism , COVID-19/immunology , COVID-19/metabolism , COVID-19/physiopathology , Comorbidity , Diabetes Mellitus, Type 2/epidemiology , Estrogen Replacement Therapy , Estrogens/immunology , Estrogens/therapeutic use , Female , Hormone Replacement Therapy , Humans , Hypertension/epidemiology , Male , Myocardial Ischemia/epidemiology , Obesity/epidemiology , Postmenopause/metabolism , Pulmonary Disease, Chronic Obstructive/epidemiology , Renal Insufficiency/epidemiology , Sex Distribution , Vitamin D Deficiency/epidemiology
10.
Med Hypotheses ; 144: 110296, 2020 Nov.
Article in English | MEDLINE | ID: covidwho-792856

ABSTRACT

The factors that may contribute to a COVID-19 patient remaining in the asymptomatic stage, or to the infection evolving into the more serious stages are examined. In particular, we refer to the TMPRSS2 expression profile, balance of androgen and estrogen, blood group-A and/or B, nonsynonymous mutations in ORF3, and proteins NS7b and NS8 in SARS-CoV-2. Also, we review other factors related to the susceptibility and pathogenicity of SARS-CoV-2.


Subject(s)
Asymptomatic Infections , COVID-19/genetics , Genetic Predisposition to Disease , SARS-CoV-2 , Serine Endopeptidases/genetics , Alleles , Androgens/metabolism , Angiotensin-Converting Enzyme 2/genetics , COVID-19/virology , Coronavirus RNA-Dependent RNA Polymerase , Exome , Female , Gene Expression Profiling , Histocompatibility Antigens Class I/genetics , Humans , Male , Models, Theoretical , Mutation , Open Reading Frames , Polymorphism, Single Nucleotide , Viral Nonstructural Proteins/genetics , Vitamin D/analogs & derivatives , Vitamin D/metabolism
14.
Andrology ; 9(1): 27-29, 2021 01.
Article in English | MEDLINE | ID: covidwho-377962

ABSTRACT

The coronavirus 2 (SARS-CoV-2) pandemic carries clinical, economic, and social burdens that are currently being disclosed. The key steps of virus life cycle have been recently clarified, highlighting the role of host type 2 angiotensin-converting enzyme (ACE2) and TMPRSS2 serine protease in virus-cell binding and entry, respectively. Importantly, major concerns derive from the androgen-dependent tissue-expression of both TMPRSS2 and ACE2, suggesting a differential clinical course of the infection between genders. In agreement with this model, available epidemiological data show that the disease in males has an higher risk to display an heavier pattern and associates with both an increased access to critical care unit and higher mortality rate. In this opinion article, available evidence linking the androgen activity with the gender differences observed in SARS-CoV-2 infection are discussed, hypothesizing possible therapeutic approaches in male based on the disruption of androgen signaling. On these bases, gender-specific recommendations for the management of male patients affected by SARS-CoV-2 infection are warmly suggested, in order to improve the clinical course of the disease.


Subject(s)
COVID-19/therapy , Health Status Disparities , SARS-CoV-2/pathogenicity , Androgens/metabolism , Angiotensin-Converting Enzyme 2/metabolism , Animals , COVID-19/diagnosis , COVID-19/metabolism , COVID-19/virology , Host-Pathogen Interactions , Humans , Male , Receptors, Virus/metabolism , Risk Factors , Serine Endopeptidases/metabolism , Sex Factors
15.
Int J Mol Sci ; 21(10)2020 May 21.
Article in English | MEDLINE | ID: covidwho-327277

ABSTRACT

The COVID-19 pandemic is marked by a wide range of clinical disease courses, ranging from asymptomatic to deadly. There have been many studies seeking to explore the correlations between COVID-19 clinical outcomes and various clinical variables, including age, sex, race, underlying medical problems, and social habits. In particular, the relationship between smoking and COVID-19 outcome is controversial, with multiple conflicting reports in the current literature. In this study, we aim to analyze how smoking may affect the SARS-CoV-2 infection rate. We analyzed sequencing data from lung and oral epithelial samples obtained from The Cancer Genome Atlas (TCGA). We found that the receptor and transmembrane protease necessary for SARS-CoV-2 entry into host cells, ACE2 and TMPRSS2, respectively, were upregulated in smoking samples from both lung and oral epithelial tissue. We then explored the mechanistic hypothesis that smoking may upregulate ACE2 expression through the upregulation of the androgen pathway. ACE2 and TMPRSS2 upregulation were both correlated to androgen pathway enrichment and the specific upregulation of central pathway regulatory genes. These data provide a potential model for the increased susceptibility of smoking patients to COVID-19 and encourage further exploration into the androgen and tobacco upregulation of ACE2 to understand the potential clinical ramifications.


Subject(s)
Androgens/metabolism , Coronavirus Infections/metabolism , Peptidyl-Dipeptidase A/genetics , Pneumonia, Viral/metabolism , Serine Endopeptidases/genetics , Smoking/metabolism , Up-Regulation , Alveolar Epithelial Cells/metabolism , Angiotensin-Converting Enzyme 2 , COVID-19 , Coronavirus Infections/epidemiology , Coronavirus Infections/genetics , Humans , Mouth Mucosa/metabolism , Pandemics , Peptidyl-Dipeptidase A/metabolism , Pneumonia, Viral/epidemiology , Pneumonia, Viral/genetics , Receptors, Androgen/genetics , Receptors, Androgen/metabolism , Serine Endopeptidases/metabolism , Smoking/epidemiology , Smoking/genetics
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