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

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 alpha (ER alpha)/androgen receptor (AR) ratio that led to increased antiviral factor levels. In male mice, inhaling recombinant ACE2 neutralized the virus and maintained the ER alpha/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 ER alpha-associated protective mechanisms. Additionally, our study supports the potential effectiveness of recombinant ACE2 therapy in human lung organoids infected with the Delta variant.

Automated summary

Despite similar infection rates, COVID-19 has resulted in more deaths in men than women. A study on K18-human angiotensin converting enzyme 2 (ACE2) mice infected with SARS-CoV-2 showed that female mice had a unique protein expression profile in the lung microenvironment, making them less vulnerable to severe infection. In contrast, male mice benefited from inhaling recombinant ACE2, which neutralized the virus and protected the lungs by maintaining a certain receptor ratio.