Is Sex a Determinant of COVID-19 Infection? Truth or Myth? (original) (raw)
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International Journal of Molecular Sciences, 2020
Severe acute respiratory syndrome coronavirus (SARS-CoV-2) disease (COVID-19) appears to have a higher mortality rate in presence of comorbidities and in men. The latter suggests the presence of a possible sex-dependent susceptibility. An enzymatic system involved in this different predisposition could be represented by angiotensin converting enzyme 2 (ACE2). ACE2 is activated and down-regulated by the spike protein of the virus and allows the penetration of SARS-CoV-2 into epithelial cells and myocardium. Data on the experimental animal have shown that 17ß-estradiol increases the expression and activity of ACE2 in both adipose tissue and kidney. Spontaneously hypertensive male mice have a higher myocardial ACE2 expression than females and its levels decrease after orchiectomy. In addition to this first aspect, the recent evidence of an increased frequency of venous thromboembolism in patients with COVID-19 (a clinical element associated with a worse prognosis) calls the attention o...
Sex differences in COVID-19: candidate pathways, genetics of ACE2, and sex hormones
American Journal of Physiology-heart and Circulatory Physiology, 2021
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.
The Physiological Mechanisms of the Sex-Based Difference in Outcomes of COVID19 Infection
Frontiers in Physiology, 2021
The scale of the SARS-CoV-2 pandemic has thrust a spotlight on the sex-based differences in response to viral diseases; morbidity and mortality are greater in men than women. We outline the mechanisms by which being female offers a degree of protection from COVID19, that persists even when confounders such as comorbidities are considered. The physiological and immunological mechanisms are fascinating and range from incomplete X chromosome inactivation of immune genes, a crucial role for angiotensin converting enzyme 2 (ACE2), and regulation of both immune activity and ACE2 by sex steroids. From this flows understanding of why lung and other organs are more susceptible to COVID19 damage in men, and how their distinct immunological landscapes need to be acknowledged to guide prognosis and treatment. Pregnancy, menopause, and hormone replacement therapy bring changed hormonal environments and the need for better stratification in COVID19 studies. We end by noting clinical trials based ...
Physiological implications of COVID-19 in reproduction: angiotensin-converting enzyme 2 a key player
Reproduction, Fertility and Development, 2021
The COVID-19 outbreak, caused by severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2), was first identified in China, and it has quickly become a global threat to public health due to its rapid rate of transmission and fatalities. Angiotensin-converting enzyme 2 (ACE2) has been identified as a receptor that mediates the entry of SARS-CoV-2 into human cells, as in the case of severe acute respiratory syndrome coronavirus (SARS-CoV). Several studies have reported that ACE2 expression is higher in Leydig, Sertoli and seminiferous ductal cells of males, as well as in ovarian follicle cells of females, suggesting possible potential pathogenicity of the coronavirus in the reproductive system. Higher ACE2 expression in the human placenta and reports of vertical transmission of SARS-CoV-2 among clinical cases have increased the relevance of further studies in this area. This review focuses on the interaction between SARS-CoV-2 and the ACE2 receptor and speculates on the mechanistic interplay in association with male and female reproductive physiology. In addition, based on the available literature, we discuss the alleged sex differences in terms of the infectivity of SARS-CoV-2, which is claimed greater among males, and further explore the physiological role of ACE2 and 17b-oestradiol for the same.
Molecular and Biological Mechanisms Underlying Gender Differences in COVID-19 Severity and Mortality
Frontiers in Immunology, 2021
Globally, over two million people have perished due to the recent pandemic caused by SARS-CoV-2. The available epidemiological global data for SARS-CoV-2 portrays a higher rate of severity and mortality in males. Analyzing gender differences in the host mechanisms involved in SARS-CoV-2 infection and progression may offer insight into the more detrimental disease prognosis and clinical outcome in males. Therefore, we outline sexual dimorphisms which exist in particular host factors and elaborate on how they may contribute to the pronounced severity in male COVID-19 patients. This includes disparities detected in comorbidities, the ACE2 receptor, renin-angiotensin system (RAS), signaling molecules involved in SARS-CoV-2 replication, proteases which prime viral S protein, the immune response, and behavioral considerations. Moreover, we discuss sexual disparities associated with other viruses and a possible gender-dependent response to SARS-CoV-2 vaccines. By specifically highlighting ...
Sex-derived attributes contributing to SARS-CoV-2 mortality
American Journal of Physiology-Endocrinology and Metabolism, 2020
Epidemiological data in COVID-19 mortality indicate that men are more prone to die of SARS-CoV-2 infection than women, but biological causes for this sexual dimorphism are unknown. We discuss the prospective behavioral and biological differences between the sexes that could be attributed to this sex-based differentiation. The female sex hormones and the immune stimulatory genes, including Toll-like receptors, interleukins, and micro-RNAs present on X-chromosome, may impart lesser infectivity and mortality of the SARS-CoV-2 in females over males. The sex hormone estrogen interacts with the renin-angiotensin-aldosterone system, one of the most critical pathways in COVID-19 infectivity, and modulates the vasomotor homeostasis. Testosterone on the contrary enhances the levels of the two most critical molecules, angiotensin-converting enzyme 2 (ACE2) and the transmembrane protease serine-type 2 (TMPRSS2), transcriptionally and posttranslationally, thereby increasing viral load and delayi...
Pathogens
The novel coronavirus disease 2019 (COVID-19) pandemic has led to an unprecedented threat to the international community and raised major concerns in terms of public health safety. Although our current understanding of the complexity of COVID-19 pathogenesis remains limited, the infection is largely mediated by the interaction of viral spike protein and angiotensin-converting enzyme 2 (ACE2). The functional importance of ACE2 in different demographic and comorbid conditions may explain the significant variation in incidence and mortality of COVID-19 in vulnerable groups, and highlights its candidacy as a potential therapeutic target. We provide evidence supporting the idea that differences in incidence and severity of COVID-19 infection may be related to ACE2. Emerging data based on the prevalence and severity of COVID-19 among those with established high levels of ACE2 expression strongly support our hypothesis. Considering the burden of COVID-19 infection in these vulnerable group...
Open Access Macedonian Journal of Medical Sciences, 2020
Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) uses the angiotensin-converting enzyme 2 (ACE2) receptor of SARS-CoV for cell entry We aimed to check the association between ACE2 and COVID-19 (coronavirus disease 2019) in a systematic review Two databases (PubMed/Medline and Scopus) and bioRxiv were checked for retrieving all types of studies in relation to ACE2 and COVID-19 until March 18, 2020 Forty-one studies were entered to the systematic review These studies included nineteen original, eight reviews, four letters to the editor, three research papers, one correspondence, one commentary, one mini review, two reports, one opinion, and one perspective In summary, the results showed that the ACE2 receptor for COVID-19 is similar to that of SARS-CoV However, its expression was different in various populations as well as in the two genders ACE2 may be used as a therapeutic target Patients who take ACE inhibitors may have benefit in severe disease outcomes Finally, pangol...
Journal of Advances in Internal Medicine
COVID-19, caused by the severe acute respiratory syndrome coronavirus (SARS-CoV-2), was first identified in China in late 2019 and since then, this disease has become a pandemic affecting many countries across the globe. Due to this outbreak, many researchers have been diligently investigating this disease for the establishment of better methods of its treatment and control. Evidence from research has led to a plethora of valuable but uncertain information on the modes of transmission of COVID-19 and the mechanisms by which SARS-CoV-2 establishes infections in targeted tissues. It is now better understood that in this disease, SARS-CoV-2 gains entrance into cells by specifically binding ACE-2 (angiotensin-converting enzyme 2); ACE-2 serves as a potential receptor for the virus. The lungs, in addition to many other organs and tissues, express ACE-2 in varying degrees. Therefore, this review will examine the role of ACE-2 in COVID-19 and the secondary effects that COVID-19 has on orga...
Frontiers in Global Women's Health, 2021
The incidence of SARS-CoV2 infections is around 15% higher in premenopausal women compared to age matched men, yet the fatality rate from COVID-19 is significantly higher in men than women for all age strata. Sex differences have also been observed in recent epidemics including severe acute respiratory syndrome (SARS) and Middle East respiratory syndrome (MERS), with SARS-CoV 2 virus infection sex differences appear more dramatic. The regulation and expression of the angiotensin converting enzyme 2 (ACE2) is the key for this special coronavirus SARS-CoV-2 to enter the cell. 17β-oestradiol increases expression level and activity of angiotensin converting enzyme-2 (ACE2) and the alternative signaling pathway of Ang II via the angiotensin II receptor type II (AT2R) and the Mas receptor is more dominant in female sex than in male sex. Maybe a hint to explain the higher infection risk in women. The same hormonal milieu plays a major role in protecting women where morbidity and mortality ...