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

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.

Cell therapy strategies for COVID-19: Current approaches and potential applications

“…It has been indicated that neuropilin 1 (NRP1) has a role in potentiating SARS-CoV-2 entry through the ACE2 pathway (6,7). Studies from other coronaviruses provided evidence for CD147 and the 78-kDa glucose-regulated protein (GRP78) as putative alternative receptors, but more investigations on how the collective tissue distribution of these factors correlate with viral tropism and disease symptoms are under active investigation (8,9).…”

Structural and functional impact by SARS-CoV-2 Omicron spike mutations

“…This observation can account for the reduced fusion activity when compared with other variants under the same conditions. It can also explain why Omicron replicates better in the upper respiratory tract than lung as the former has much higher levels of ACE2 (51,52). The transition from the closed to the RBD-up conformation in an S trimer typically requires an order-disorder transition in the FPPR and 630 loop.…”

Immune Cells Profiles in the Different Sites of COVID-19-Affected Lung Lobes in a Single Patient

“…SARS-CoV-2 enters host cells, such as respiratory epithelial cells, by binding to ACE2, which is a type I transmembrane glycoprotein with carboxypeptidase activity; however, the abundance and distribution of ACE2 in human lungs are elusive. For instance, ACE2 is expressed at high levels in alveolar type II cells (AT2s) ( 20 ), which are rare ciliated epithelial and endothelial cells present in the trachea, but not in the lungs ( 21 ). In other studies, AT2 as well as ciliated cells in human lungs were shown to express ACE2 ( 22 ).…”