Structural and Functional Analysis of Female Sex Hormones Against SARS-CoV2 Cell Entry

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.