Molecular Mechanisms Lead to Sex-Specific COVID-19 Prognosis and Targeted Therapies

Abstract

Clinical and epidemiological studies have identified male sex as an important risk factor for COVID-19 clinical outcomes and mortality. This raises the question as to how this risk factor can be addressed in the prognosis, clinical management, and the treatment of patients with Coronavirus disease 2019 (COVID-19). Currently, there are no guidelines or protocols to help alter the course of sex-specific COVID-19 prognosis, especially in severe disease presentations. This is partly due to the lack of research studies characterizing the differences in male vs. female host response to the severe acute respiratory syndrome Coronavirus-2 (SARS-CoV-2) infection and a lack of a well-rounded understanding of the molecular mechanisms involved. Here, we discuss three distinct but interconnected molecular-level differences in males and females that likely play an essential role in the COVID-19 prognosis. We review interactions of SARS-CoV-2 with host cell angiotensin-converting enzyme 2 (ACE2) in the viral entry between males vs. females and discuss the differential regulation of the renin-angiotensin system (RAS) between the two sexes. Next, we present immune response disparities and how immune function and endocrine regulation may render males increasingly vulnerable to severe COVID-19. We describe the interconnected roles of these three regulatory systems in males and females in response to SARS-CoV-2 infection. Finally, we highlight the clinical implications of these mechanisms to patients with COVID-19 and propose putative targeted therapies that can help reduce COVID-19 severity in those critically ill.

Keywords: ACE2; SARS-CoV-2; androgen; coronavirus; endocrine; immunity; male; sex.

Figure 1

Male and female display differences in COVID-19 severity. The differences in disease severity can be explained by sex-specific differences in the regulation of ACE2, immune response, and endocrine regulation. These distinct but interconnected molecular mechanisms lead to severe COVID-19 in men.

Figure 2

The role of ACE2 receptors in modulating COVID-19 severity. Angiotensin-converting enzyme 2 (ACE2) plays a central role in the observed sex-specific disparities in COVID-19 severity. ACE2 is the receptor for viral cell entry. Transmembrane protease, serine 2 (TMPRSS2), is needed for priming of the viral S protein to allow viral cell entry. The transcription of TMPRSS2 is under the control of the Androgen Receptor (AR), which is located on the X chromosome (Xq12). With SARS-CoV-2 entry into the host cell, ACE2 is downregulated. In the absence of ACE2, angiotensin-II (Ang-II) cannot be cleaved to give angiotensin-(1-7) [Ang-(1-7)], and the action of Ang-II increases. Activation of angiotensin type 1 receptor (AT1R) by Ang-II leads to more inflammation, vasoconstriction, fibrosis, vascular permeability, and acute lung injury and results in severe COVID-19. The ACE2 gene is located on the X chromosome (Xp22.2) and is regulated by estrogen. Estrogen causes increased levels of ACE2, which cleaves Ang-II to Ang-(1-7). Ang-(1-7) activates the mitochondrial assembly receptor (Mas R). This causes anti-inflammation, vasodilation, reduced fibrosis, hypotension, and less lung injury, leading to a less severe form of COVID-19. Outcomes highlighted in blue are associated more with males, and those highlighted in red are associated more with females. This figure was created with the images available at Servier Medical Art, licensed under a Creative Commons Attribution 3.0 Unported License.