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 observed 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-CoV2 thereby blocking its entry into cells. In a mouse model, 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.Funding: Dr. Lino Cardenas is supported by the MGH Physician-Scientist Development Award and the MGH Department of Medicine Pilot Translational Research Grant. Dr. Malhotra is supported by a COVID-19 Fast Grant (fastgrants.org), NHLBI R01 HL142809, the American Heart Association grant 18TPA34230025, and the Wild Family Foundation. Dr. Lindsay is supported by the Fredman Fellowship, the Toomey Fund for Aortic Dissection Research, the Hassenfeld Fellowship and NIH/NHLBI R01HL130113. Dr. Davila-Del Carpio, Dr. Aguilar Pineda and Dr. Vera Lopez are supported by the COVID-19 Fast Grant (0371-VRINV-2020) from the Vicerrectorado de Investigación de la Universidad Católica de Santa María, Arequipa, Peru. Conflict of Interest: Authors declare no competing interests.Ethical Approval: All experiments involving mice were approved by the Partners Subcommittee on Research Animal Care. Personnel from the laboratory carried out all experimental protocols under strict guidelines to insure careful and consistent handling of the mice.
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
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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