Inhalation of ACE2 as a therapeutic target on sex-bias differences in SARS-CoV-2 infection and variant of concern

Yu Onodera; Jady Liang; Yuchong Li; Bryan Griffin; Thenuka Thanabalasingam; Cong Lu; JiaYi Zhu; Mingyao Liu; Theo Moraes; Wenhua Zheng; Jasmin Khateeb; Julie Khang; Yongbo Huang; Mirjana Jerkic; Masaki Nakane; Andrew Baker; Beverley Orser; Ya-Wen Chen; Gerald Wirnsberger; Josef M Penninger; Ori D Rotstein; Arthur S Slutsky; Yimin Li; Samira Mubareka; Haibo Zhang

doi:10.1016/j.isci.2023.107470

Inhalation of ACE2 as a therapeutic target on sex-bias differences in SARS-CoV-2 infection and variant of concern

iScience. 2023 Jul 25;26(8):107470. doi: 10.1016/j.isci.2023.107470. eCollection 2023 Aug 18.

Authors

Yu Onodera^{1

2}, Jady Liang^{1

3}, Yuchong Li^{1

4}, Bryan Griffin^{5

6}, Thenuka Thanabalasingam¹, Cong Lu¹, JiaYi Zhu^{1

3}, Mingyao Liu⁷, Theo Moraes⁸, Wenhua Zheng⁹, Jasmin Khateeb^{1

10}, Julie Khang¹, Yongbo Huang⁴, Mirjana Jerkic¹, Masaki Nakane², Andrew Baker^{1

11

12}, Beverley Orser¹¹, Ya-Wen Chen¹³, Gerald Wirnsberger¹⁴, Josef M Penninger^{15

16}, Ori D Rotstein^{1

7}, Arthur S Slutsky^{1

4

12}, Yimin Li⁴, Samira Mubareka^{5

6}, Haibo Zhang^{1

3

4

11

12}

Affiliations

¹ Keenan Research Centre for Biomedical Science, St. Michael's Hospital, Unity Health Toronto, Toronto, ON, Canada.
² Department of Emergency and Critical Care Medicine, Faculty of Medicine, Yamagata University, Yamagata, Japan.
³ Department of Physiology, University of Toronto, Toronto, ON, Canada.
⁴ The State Key Laboratory of Respiratory Disease, Guangzhou Institute of Respiratory Disease, The First Affiliated Hospital of Guangzhou Medical University, Guangzhou, China.
⁵ Department of Laboratory Medicine and Pathobiology, University of Toronto, Toronto, ON, Canada.
⁶ Department of Medical Microbiology and Infectious Disease, Sunnybrook Health Science Centre, Toronto, ON, Canada.
⁷ Department of Surgery, University of Toronto, Toronto, ON, Canada.
⁸ Department of Pediatrics, University of Toronto, Toronto, ON, Canada.
⁹ Faculty of Health Science, University of Macau, Macau, China.
¹⁰ Department of Internal Medicine D, Rambam Health Care Campus, Haifa, Israel.
¹¹ Department of Anesthesiology and Pain Medicine, University of Toronto, Toronto, ON, Canada.
¹² Interdepartmental Division of Critical Care Medicine, University of Toronto, Toronto, ON, Canada.
¹³ Black Family Stem Cell Institute, Department of Cell, Developmental and Regenerative Biology, Icahn School of Medicine at Mount Sinai, New York city, NY, USA.
¹⁴ Apeiron Biologics AG, Campus-Vienna-Biocenter 5, Vienna, Austria.
¹⁵ Institute of Molecular Biotechnology of the Austrian Academy of Sciences, Vienna, Austria.
¹⁶ Department of Medical Genetics, Life Sciences Institute, University of British Columbia, Vancouver, BC, Canada.

Abstract

Despite similar infection rates, COVID-19 has resulted in more deaths in men than women. To understand the underlying mechanisms behind this sex-biased difference in disease severity, we infected K18-human angiotensin converting enzyme 2 (ACE2) mice of both sexes with SARS-CoV-2. Our study revealed a unique protein expression profile in the lung microenvironment of female mice. As a result, they were less vulnerable to severe infection, with higher ACE2 expression and a higher estrogen receptor α (ERα)/androgen receptor (AR) ratio that led to increased antiviral factor levels. In male mice, inhaling recombinant ACE2 neutralized the virus and maintained the ERα/AR ratio, thereby protecting the lungs. Our findings suggest that inhaling recombinant ACE2 could serve as a decoy receptor against SARS-CoV-2 and protect male mice by offsetting ERα-associated protective mechanisms. Additionally, our study supports the potential effectiveness of recombinant ACE2 therapy in human lung organoids infected with the Delta variant.

Keywords: Biological sciences; Biology of gender; Immune response; Virology.