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. Further, the ACE2 enzyme is involved in disease pathogenesis in cardiovascular disease and COVID-19, either to serve as a protective mechanism by deactivating the renin-angiotensin system 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 (ADAM)17. 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 will explore 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 will highlight the added challenges of gender in the COVID-19 pandemic.

中文翻译：

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COVID-19中的性别差异：候选途径，ACE2的遗传学和性激素

人们越来越认识到，生物性别是健康和疾病的关键决定因素，尤其是与SARS-CoV-2冠状病毒引起的局部COVID-19大流行有关。最初的SARS流行病和最近的COVID-19大流行病的流行病学数据和观察报告都有一个共同的特征：男性比女性更有可能表现出更高的疾病严重度和死亡率。心血管疾病和COVID-19的性别差异具有机制基础，即先天免疫系统和规范性肾素-血管紧张素系统（RAS）的参与。免疫学差异表明，雌性动物具有快速而积极的先天免疫反应，而雄性动物抗病毒反应减弱可能会增加其对严重疾病的敏感性。进一步，ACE2酶参与心血管疾病和COVID-19的疾病发病机理，分别通过使肾素-血管紧张素系统失活而充当保护机制或作为病毒进入的受体。膜ACE2的丢失和血浆ACE2的相应增加与心血管疾病预后恶化有关，这是归因于Disintegrin和金属蛋白酶（ADAM）17的机制。SARS-CoV-2感染还导致ADAM17激活，这是一个正反馈周期，加剧了ACE2的丢失。因此，心血管疾病和COVID-19之间的关系主要取决于ADAM17介导的蛋白水解裂解引起的ACE2膜损失。本文将探讨涉及COVID-19的潜在机制，这些机制可能会导致针对性别的易感性，重点关注先天免疫系统和RAS，即遗传和性激素。最后，我们将重点介绍COVID-19大流行中的性别挑战。