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.
Highlights
Coronavirus disease 19 (COVID-19) pandemic, caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), has accounted for more than 90 million confirmed cases and close to 2 million deaths worldwide as of January 2021
Angiotensin converting enzyme 2 (ACE2) expression is not detected in non-human primate (NHP) lungs with and without cigarette smoke-induced airway injury
Despite a plethora of studies showing ACE2 mRNA expression in various cell types in the human lung, there is controversy on the distribution and abundance of ACE2 protein expression, which has critical importance in understanding how SARS-CoV2 infection spreads to the lung [18, 19, 21, 23]
Summary
Coronavirus disease 19 (COVID-19) pandemic, caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), has accounted for more than 90 million confirmed cases and close to 2 million deaths worldwide as of January 2021. Angiotensin converting enzyme 2 (ACE2), a type I transmembrane glycoprotein with carboxypeptidase activity, has been proposed to be the key functional receptor for SARS-CoV-2 [3, 4]. During the COVID-19 pandemic, it was reported by several groups that SARS-CoV-2 depends on ACE2 for entry into host cells [4,5,6,7]. While these studies have provided definitive evidence that ACE2 is a receptor for both SARS coronaviruses, whether it is the functional receptor in target respiratory epithelial cells remains to be verified
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