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, Yuchong Li, Bryan D. Griffin, Thenuka Thanabalasingam, Cong Lu, Jiayi Zhu, Mingyao Liu, Theo J. Moraes, Wenhua Zheng, Jasmin Khateeb, Julie Khang, Yongbo Huang, Mirjana Jerkić, Masaki Nakane, Andrew Baker, Beverley A. Orser, Ya‐Wen Chen, Gerald Wirnsberger, Josef Penninger, Ori D. Rotstein, Arthur S. Slutsky, Yimin Li, Yimin Li, Samira Mubareka, Haibo Zhang
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.