Heterogeneous expression of the SARS-Coronavirus-2 receptor ACE2 in the human respiratory tract.

Miguel E Ortiz,Alejandro A Pezzulo,Andrew Thurman,Julia A Klesney-Tait,Philip H Karp,Christine Wohlford-Lenane,David K Meyerholz,Paul B Mccray,Mariah R Leidinger,Ping Tan

doi:10.1016/j.ebiom.2020.102976

Abstract

BackgroundZoonotically transmitted coronaviruses are responsible for three disease outbreaks since 2002, including the current COVID-19 pandemic, caused by SARS-CoV-2. Its efficient transmission and range of disease severity raise questions regarding the contributions of virus-receptor interactions. ACE2 is a host ectopeptidase and the receptor for SARS-CoV-2. Numerous reports describe ACE2 mRNA abundance and tissue distribution; however, mRNA abundance is not always representative of protein levels. Currently, there is limited data evaluating ACE2 protein and its correlation with other SARS-CoV-2 susceptibility factors.Materials and methodsWe systematically examined the human upper and lower respiratory tract using single-cell RNA sequencing and immunohistochemistry to determine receptor expression and evaluated its association with risk factors for severe COVID-19.FindingsOur results reveal that ACE2 protein is highest within regions of the sinonasal cavity and pulmonary alveoli, sites of presumptive viral transmission and severe disease development, respectively. In the lung parenchyma, ACE2 protein was found on the apical surface of a small subset of alveolar type II cells and colocalized with TMPRSS2, a cofactor for SARS-CoV2 entry. ACE2 protein was not increased by pulmonary risk factors for severe COVID-19. Additionally, ACE2 protein was not reduced in children, a demographic with a lower incidence of severe COVID-19.InterpretationThese results offer new insights into ACE2 protein localization in the human respiratory tract and its relationship with susceptibility factors to COVID-19.

Highlights

Angiotensin-converting enzyme 2 (ACE2) is the cellular receptor for both severe acute respiratory syndrome coronavirus (SARS-CoV) and SARS-CoV-2 [1,2]
Alveolar macrophages were negative for ACE2 protein staining by immunohistochemistry, despite previous reports of ACE2 protein in these cells (Supplemental Table 1)
In vitro studies demonstrate that ACE2 protein is found at the apical membrane of polarized airway epithelia, where it permits virus binding and cell entry [21,30]

Summary

Introduction

Angiotensin-converting enzyme 2 (ACE2) is the cellular receptor for both severe acute respiratory syndrome coronavirus (SARS-CoV) and SARS-CoV-2 [1,2]. SARS-CoV-2 infection can be fatal, with the risk for increased disease severity correlating with advanced age and underlying comorbidities, while children and younger individuals generally have milder disease [5À11] These trends in disease severity could reflect differences in ACE2 distribution and expression in the respiratory tract. Research in context: Evidence before this study: Previous studies of ACE2 mRNA transcript abundance in the human respiratory tract have suggested a possible association between ACE2 expression and age, sex, and the presence of comorbidities. These studies have provided conflicting results, as well as a lack of protein validation. Interpretation: These results offer new insights into ACE2 protein localization in the human respiratory tract and its relationship with susceptibility factors to COVID-19

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Results

Conclusion