Comparative analysis of ACE2 protein expression in rodent, non-human primate, and human respiratory tract at baseline and after injury: A conundrum for COVID-19 pathogenesis
Open Access
- 24 February 2021
- journal article
- research article
- Published by Public Library of Science (PLoS) in PLOS ONE
- Vol. 16 (2), e0247510
- https://doi.org/10.1371/journal.pone.0247510
Abstract
Angiotensin converting enzyme 2 (ACE2) is the putative functional receptor for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Current literature on the abundance and distribution of ACE2 protein in the human respiratory tract is controversial. We examined the effect of age and lung injury on ACE2 protein expression in rodent and non-human primate (NHP) models. We also examined ACE2 expression in human tissues with and without coronavirus disease 19 (COVID-19). ACE2 expression was detected at very low levels in preterm, but was absent in full-term and adult NHP lung homogenates. This pattern of ACE2 expression contrasted with that of transmembrane protease serine type 2 (TMPRSS2), which was significantly increased in full-term newborn and adult NHP lungs compared to preterm NHP lungs. ACE2 expression was not detected in NHP lungs with cigarette smoke-induced airway disease or bronchopulmonary dysplasia. Murine lungs lacked basal ACE2 immunoreactivity, but responded to hyperoxia, bacterial infection, and allergen exposure with new ACE2 expression in bronchial epithelial cells. In human specimens, robust ACE2 immunoreactivity was detected in ciliated epithelial cells in paranasal sinus specimens, while ACE2 expression was detected only in rare type 2 alveolar epithelial cells in control lungs. In autopsy specimens from patients with COVID-19 pneumonia, ACE2 was detected in rare ciliated epithelial and endothelial cells in the trachea, but not in the lung. There was robust expression of ACE2 expression in F344/N rat nasal mucosa and lung specimens, which authentically recapitulated the ACE2 expression pattern in human paranasal sinus specimens. Thus, ACE2 protein expression demonstrates a significant gradient between upper and lower respiratory tract in humans and is scarce in the lung. This pattern of ACE2 expression supports the notion of sinonasal epithelium being the main entry site for SARS-CoV-2 but raises further questions on the pathogenesis and cellular targets of SARS-CoV-2 in COVID-19 pneumonia.Keywords
Funding Information
- National Institute of Child Health and Human Development (5R21HD092934)
- National Heart, Lung, and Blood Institute (UO1HL075904)
- Brigham Research Institute
- National Institutes of Health (RO1 HL68111)
This publication has 47 references indexed in Scilit:
- Adam8 Limits the Development of Allergic Airway Inflammation in MiceThe Journal of Immunology, 2013
- Influenza and SARS-Coronavirus Activating Proteases TMPRSS2 and HAT Are Expressed at Multiple Sites in Human Respiratory and Gastrointestinal TractsPLOS ONE, 2012
- Hyperoxia-Induced LC3B Interacts with the Fas Apoptotic Pathway in Epithelial Cell DeathAmerican Journal of Respiratory Cell and Molecular Biology, 2012
- Fatty Acid–Binding Proteins and Peribronchial Angiogenesis in Bronchopulmonary DysplasiaAmerican Journal of Respiratory Cell and Molecular Biology, 2011
- Fatty acid binding protein 4 is a target of VEGF and a regulator of cell proliferation in endothelial cellsThe FASEB Journal, 2009
- Imbalance between Cysteine Proteases and Inhibitors in a Baboon Model of Bronchopulmonary DysplasiaAmerican Journal of Respiratory and Critical Care Medicine, 2006
- Bcl-2 Sustains Increased Mucous and Epithelial Cell Numbers in Metaplastic Airway EpitheliumAmerican Journal of Respiratory and Critical Care Medicine, 2005
- Tissue distribution of ACE2 protein, the functional receptor for SARS coronavirus. A first step in understanding SARS pathogenesisThe Journal of Pathology, 2004
- Angiotensin-converting enzyme 2 is a functional receptor for the SARS coronavirusNature, 2003
- Coronavirus Spike Proteins in Viral Entry and PathogenesisVirology, 2001