iScience (Aug 2023)
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
Affiliations
- Yu Onodera
- Keenan Research Centre for Biomedical Science, St. Michael’s Hospital, Unity Health Toronto, Toronto, ON, Canada; Department of Emergency and Critical Care Medicine, Faculty of Medicine, Yamagata University, Yamagata, Japan
- Jady Liang
- Keenan Research Centre for Biomedical Science, St. Michael’s Hospital, Unity Health Toronto, Toronto, ON, Canada; Department of Physiology, University of Toronto, Toronto, ON, Canada
- Yuchong Li
- Keenan Research Centre for Biomedical Science, St. Michael’s Hospital, Unity Health Toronto, Toronto, ON, Canada; The State Key Laboratory of Respiratory Disease, Guangzhou Institute of Respiratory Disease, The First Affiliated Hospital of Guangzhou Medical University, Guangzhou, China
- Bryan Griffin
- Department of Laboratory Medicine and Pathobiology, University of Toronto, Toronto, ON, Canada; Department of Medical Microbiology and Infectious Disease, Sunnybrook Health Science Centre, Toronto, ON, Canada
- Thenuka Thanabalasingam
- Keenan Research Centre for Biomedical Science, St. Michael’s Hospital, Unity Health Toronto, Toronto, ON, Canada
- Cong Lu
- Keenan Research Centre for Biomedical Science, St. Michael’s Hospital, Unity Health Toronto, Toronto, ON, Canada
- JiaYi Zhu
- Keenan Research Centre for Biomedical Science, St. Michael’s Hospital, Unity Health Toronto, Toronto, ON, Canada; Department of Physiology, University of Toronto, Toronto, ON, Canada
- Mingyao Liu
- Department of Surgery, University of Toronto, Toronto, ON, Canada
- Theo Moraes
- Department of Pediatrics, University of Toronto, Toronto, ON, Canada
- Wenhua Zheng
- Faculty of Health Science, University of Macau, Macau, China
- Jasmin Khateeb
- Keenan Research Centre for Biomedical Science, St. Michael’s Hospital, Unity Health Toronto, Toronto, ON, Canada; Department of Internal Medicine D, Rambam Health Care Campus, Haifa, Israel
- Julie Khang
- Keenan Research Centre for Biomedical Science, St. Michael’s Hospital, Unity Health Toronto, Toronto, ON, Canada
- Yongbo Huang
- The State Key Laboratory of Respiratory Disease, Guangzhou Institute of Respiratory Disease, The First Affiliated Hospital of Guangzhou Medical University, Guangzhou, China
- Mirjana Jerkic
- Keenan Research Centre for Biomedical Science, St. Michael’s Hospital, Unity Health Toronto, Toronto, ON, Canada
- Masaki Nakane
- Department of Emergency and Critical Care Medicine, Faculty of Medicine, Yamagata University, Yamagata, Japan
- Andrew Baker
- Keenan Research Centre for Biomedical Science, St. Michael’s Hospital, Unity Health Toronto, Toronto, ON, Canada; Department of Anesthesiology and Pain Medicine, University of Toronto, Toronto, ON, Canada; Interdepartmental Division of Critical Care Medicine, University of Toronto, Toronto, ON, Canada
- Beverley Orser
- Department of Anesthesiology and Pain Medicine, University of Toronto, Toronto, ON, Canada
- Ya-Wen Chen
- Black Family Stem Cell Institute, Department of Cell, Developmental and Regenerative Biology, Icahn School of Medicine at Mount Sinai, New York city, NY, USA
- Gerald Wirnsberger
- Apeiron Biologics AG, Campus-Vienna-Biocenter 5, Vienna, Austria
- Josef M. Penninger
- Institute of Molecular Biotechnology of the Austrian Academy of Sciences, Vienna, Austria; Department of Medical Genetics, Life Sciences Institute, University of British Columbia, Vancouver, BC, Canada
- Ori D. Rotstein
- Keenan Research Centre for Biomedical Science, St. Michael’s Hospital, Unity Health Toronto, Toronto, ON, Canada; Department of Surgery, University of Toronto, Toronto, ON, Canada
- Arthur S. Slutsky
- Keenan Research Centre for Biomedical Science, St. Michael’s Hospital, Unity Health Toronto, Toronto, ON, Canada; The State Key Laboratory of Respiratory Disease, Guangzhou Institute of Respiratory Disease, The First Affiliated Hospital of Guangzhou Medical University, Guangzhou, China; Interdepartmental Division of Critical Care Medicine, University of Toronto, Toronto, ON, Canada
- Yimin Li
- The State Key Laboratory of Respiratory Disease, Guangzhou Institute of Respiratory Disease, The First Affiliated Hospital of Guangzhou Medical University, Guangzhou, China; Corresponding author
- Samira Mubareka
- Department of Laboratory Medicine and Pathobiology, University of Toronto, Toronto, ON, Canada; Department of Medical Microbiology and Infectious Disease, Sunnybrook Health Science Centre, Toronto, ON, Canada; Corresponding author
- Haibo Zhang
- Keenan Research Centre for Biomedical Science, St. Michael’s Hospital, Unity Health Toronto, Toronto, ON, Canada; Department of Physiology, University of Toronto, Toronto, ON, Canada; The State Key Laboratory of Respiratory Disease, Guangzhou Institute of Respiratory Disease, The First Affiliated Hospital of Guangzhou Medical University, Guangzhou, China; Department of Anesthesiology and Pain Medicine, University of Toronto, Toronto, ON, Canada; Interdepartmental Division of Critical Care Medicine, University of Toronto, Toronto, ON, Canada; Corresponding author
- Journal volume & issue
-
Vol. 26,
no. 8
p. 107470
Abstract
Summary: 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.
