Human ACE2 expression, a major tropism determinant for SARS-CoV-2, is regulated by upstream and intragenic elements

Abstract

Angiotensin-converting enzyme 2 (ACE2), part of the renin-angiotensin system (RAS), serves as an entry point for SARS-CoV-2, leading to viral proliferation in permissive cell types. Using mouse lines in which the Ace2 locus has been humanized by syntenic replacement, we show that regulation of basal and interferon induced ACE2 expression, relative expression levels of different ACE2 transcripts, and sexual dimorphism in ACE2 expression are unique to each species, differ between tissues, and are determined by both intragenic and upstream promoter elements. Our results indicate that the higher levels of expression of ACE2 observed in the lungs of mice relative to humans may reflect the fact that the mouse promoter drives expression of ACE2 in populous airway club cells while the human promoter drives expression in alveolar type 2 (AT2) cells. In contrast to transgenic mice in which human ACE2 is expressed in ciliated cells under the control of the human FOXJ1 promoter, mice expressing ACE2 in club cells under the control of the endogenous Ace2 promoter show a robust immune response after infection with SARS-CoV-2, leading to rapid clearance of the virus. This supports a model in which differential expression of ACE2 determines which cell types in the lung are infected, and this in turn modulates the host response and outcome of COVID-19.

Angiotensin-converting enzyme 2: virus accomplice or host defender?

“…[74] In addition, John et al reported that the expression of ACE2 not only determines whether an individual is infected but also in turn regulates the host’s response and outcome. [75] In conclusion, ACE2 is a potential target for the treatment of patients infected with SARS-CoV-2, which provides a new perspective for targeting the corresponding receptor protein in the treatment of viral infections.…”

Vaccine-mediated protection against Merbecovirus and Sarbecovirus challenge in mice

“…The trivalent RBD scNP vaccine is a viable strategy for vaccine-mediated protection against the three highly pathogenic group 2b and 2c betacoronaviruses—SARS-CoV, SARS-CoV-2 and its variants, and MERS-CoV. Moving forward, it will be critical to assess if this trivalent RBD scNP vaccine also protects against group 2b and 2c coronaviruses in additional mouse models that express hACE2 in the upper and lower airway epithelium, as is observed in humans 32 and in other MERS-CoV mouse challenge models. 33 …”

Vaccine-mediated protection against merbecovirus and sarbecovirus challenge in mice

“…The trivalent RBD scNP vaccine is a viable strategy for vaccinemediated protection against the three highly pathogenic group 2b and 2c betacoronaviruses-SARS-CoV, SARS-CoV-2 and its variants, and MERS-CoV. Moving forward, it will be critical to assess if this trivalent RBD scNP vaccine also protects against group 2b and 2c coronaviruses in additional mouse models that express hACE2 in the upper and lower airway epithelium, as is observed in humans 32 and in other MERS-CoV mouse challenge models. 33 Limitations of the study A limitation to our study is that mucosal antibody responses were not measured.…”