Atherothrombosis and Vascular Biology Laboratory, Baker Heart and Diabetes Institute, 75 Commercial Rd, Melbourne, VIC 3004, Australia.
Molecular Imaging and Theranostics Laboratory, Baker Heart and Diabetes Institute, Melbourne, VIC, Australia.
Cardiovasc Res. 2020 Dec 1;116(14):2197-2206. doi: 10.1093/cvr/cvaa284.
The high mortality rate of Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) infection is a critical concern of the coronavirus disease 2019 (COVID-19) pandemic. Strikingly, men account for the majority of COVID-19 deaths, with current figures ranging from 59% to 75% of total mortality. However, despite clear implications in relation to COVID-19 mortality, most research has not considered sex as a critical factor in data analysis. Here, we highlight fundamental biological differences that exist between males and females, and how these may make significant contributions to the male-biased COVID-19 mortality. We present preclinical evidence identifying the influence of biological sex on the expression and regulation of angiotensin-converting enzyme 2 (ACE2), which is the main receptor used by SARS-CoV-2 to enter cells. However, we note that there is a lack of reports showing that sexual dimorphism of ACE2 expression exists and is of functional relevance in humans. In contrast, there is strong evidence, especially in the context of viral infections, that sexual dimorphism plays a central role in the genetic and hormonal regulation of immune responses, both of the innate and the adaptive immune system. We review evidence supporting that ineffective anti-SARS-CoV-2 responses, coupled with a predisposition for inappropriate hyperinflammatory responses, could provide a biological explanation for the male bias in COVID-19 mortality. A prominent finding in COVID-19 is the increased risk of death with pre-existing cardiovascular comorbidities, such as hypertension, obesity, and age. We contextualize how important features of sexual dimorphism and inflammation in COVID-19 may exhibit a reciprocal relationship with comorbidities, and explain their increased mortality risk. Ultimately, we demonstrate that biological sex is a fundamental variable of critical relevance to our mechanistic understanding of SARS-CoV-2 infection and the pursuit of effective COVID-19 preventative and therapeutic strategies.
严重急性呼吸综合征冠状病毒 2 (SARS-CoV-2) 感染的高死亡率是 2019 年冠状病毒病 (COVID-19) 大流行的一个关键关注点。引人注目的是,男性占 COVID-19 死亡人数的大多数,目前的数字范围为总死亡率的 59%至 75%。然而,尽管与 COVID-19 死亡率有明显的关联,但大多数研究并没有将性别视为数据分析的关键因素。在这里,我们强调了男性和女性之间存在的基本生物学差异,以及这些差异如何对男性偏倚的 COVID-19 死亡率产生重大影响。我们提出了临床前证据,证明了生物学性别对血管紧张素转换酶 2 (ACE2) 的表达和调节的影响,ACE2 是 SARS-CoV-2 进入细胞的主要受体。然而,我们注意到,缺乏表明 ACE2 表达的性别二态性存在且在人类中具有功能相关性的报告。相比之下,有强有力的证据表明,性别二态性在遗传和激素对固有和适应性免疫系统免疫反应的调节中起着核心作用,尤其是在病毒感染的情况下。我们回顾了支持无效的抗 SARS-CoV-2 反应,加上对不适当的过度炎症反应的倾向,可能为 COVID-19 死亡率中的男性偏倚提供生物学解释的证据。COVID-19 的一个突出发现是,存在心血管合并症(如高血压、肥胖和年龄)会增加死亡风险。我们将 COVID-19 中性别二态性和炎症的重要特征与合并症之间的相互关系进行了情境化处理,并解释了它们增加的死亡风险。最终,我们证明了生物学性别是一个基本变量,对我们对 SARS-CoV-2 感染的机制理解和追求有效的 COVID-19 预防和治疗策略具有至关重要的意义。