Structural and Functional Analysis of Female Sex Hormones against SARS-CoV-2 Cell Entry.

Jorge Alberto Aguilar-Pineda,Karla Lucia F Alvarez,Badhin Gómez,Christian L Lino Cardenas,Mazen Albaghdadi,Rita Nieto-Montesinos,Wanlin Jiang,Karin J Vera-Lopez,Rajeev Malhotra,Gonzalo Davila Del-Carpio,Mark E Lindsay

doi:10.3390/ijms222111508

Abstract

Emerging evidence suggests that males are more susceptible to severe infection by the SARS-CoV-2 virus than females. A variety of mechanisms may underlie the observed gender-related disparities including differences in sex hormones. However, the precise mechanisms by which female sex hormones may provide protection against SARS-CoV-2 infectivity remains unknown. Here we report new insights into the molecular basis of the interactions between the SARS-CoV-2 spike (S) protein and the human ACE2 receptor. We further report that glycosylation of the ACE2 receptor enhances SARS-CoV-2 infectivity. Importantly, estrogens can disrupt glycan–glycan interactions and glycan–protein interactions between the human ACE2 and the SARS-CoV-2 thereby blocking its entry into cells. In a mouse model of COVID-19, estrogens reduced ACE2 glycosylation and thereby alveolar uptake of the SARS-CoV-2 spike protein. These results shed light on a putative mechanism whereby female sex hormones may provide protection from developing severe infection and could inform the development of future therapies against COVID-19.

Highlights

The novel coronavirus disease 2019 (COVID-19) global pandemic caused by infection with the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) virus has infected nearly 200 million people worldwide resulting in nearly 5 million deaths as of 21 September 2021
Besides the epidemiologic evidence suggesting that females are protected from severe infection, a recent study has demonstrated that the female reproductive tract expresses very low levels of the angiotensin converting enzyme 2 (ACE2) receptor and almost undetectable TMPRSS2, suggesting that the virus is unlikely to infect the female reproductive tract, where female sex hormones are produced [27,28]
We utilized in silico, in vitro, and in vivo studies to characterize important glycosylation-mediated interactions between the SARS-CoV-2 virus spike (S) protein and the human ACE2 receptor that can be modulated by endogenous or dietary estrogens in a manner that may be protective against the SARS-CoV-2 entry into human cells

Summary

Introduction

The novel coronavirus disease 2019 (COVID-19) global pandemic caused by infection with the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) virus has infected nearly 200 million people worldwide resulting in nearly 5 million deaths as of 21 September 2021. Emerging data suggests that males are more susceptible to COVID-19 infection and are at higher risk of critical illness and death than females [1,2,3]. It has been postulated that the male-biased sex divergence in COVID-19 deaths could be, in part, explained by the strict relationship between sex hormones and the expression of the entry receptor for SARS-CoV-2, the angiotensin converting enzyme 2 (ACE2) receptor [2,8]. Molecular studies have demonstrated that the male hormone testosterone regulates the expression of ACE2 and the transmembrane serine protease 2 (TMPRSS2) which is an androgen-responsive serine protease that cleaves the SARS-CoV-2 spike (S) protein and facilitates viral entry via ACE2 binding [9,10,11]. Androgen-driven upregulation of ACE2 levels may be associated with increased vulnerability to severe infections in male patients with COVID-19. ACE2 plays an important role in lung protection during injury which is attenuated by the binding of SARS-CoV-2 [12]

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Results

Conclusion