ACE2 localizes to the respiratory cilia and is not increased by ACE inhibitors or ARBs

Abstract

The coronavirus SARS-CoV-2 is the causative agent of the ongoing severe acute respiratory disease pandemic COVID-19. Tissue and cellular tropism is one key to understanding the pathogenesis of SARS-CoV-2. We investigate the expression and subcellular localization of the SARS-CoV-2 receptor, angiotensin-converting enzyme 2 (ACE2), within the upper (nasal) and lower (pulmonary) respiratory tracts of human donors using a diverse panel of banked tissues. Here, we report our discovery that the ACE2 receptor protein robustly localizes within the motile cilia of airway epithelial cells, which likely represents the initial or early subcellular site of SARS-CoV-2 viral entry during host respiratory transmission. We further determine whether ciliary ACE2 expression in the upper airway is influenced by patient demographics, clinical characteristics, comorbidities, or medication use, and show the first mechanistic evidence that the use of angiotensin-converting enzyme inhibitors (ACEI) or angiotensin II receptor blockers (ARBs) does not increase susceptibility to SARS-CoV-2 infection through enhancing the expression of ciliary ACE2 receptor. These findings are crucial to our understanding of the transmission of SARS-CoV-2 for prevention and control of this virulent pathogen.

SARS-CoV-2 Receptor Angiotensin I-Converting Enzyme Type 2 (ACE2) Is Expressed in Human Pancreatic β-Cells and in the Human Pancreas Microvasculature

“…On the contrary, by using two different antibodies (MAB933 and Ab15348)-which can recognize the C-terminal domain shared between short-and long-ACE2-we obtained clear and concordant results, with identification of ACE2 in pancreatic islet endocrine cells in addition to the microvasculature. As a positive control for the antibodies and our IHC procedure, MAB933 and Ab15348 were also tested in FFPE lung tissue sections, showing overlapping results with previously published studies (7,41,42).…”

“…Such subcellular localization was observed both in-vitro in EndoC-bH1 and ex vivo in b-cells of primary human pancreatic tissues. Although ACE2 has been primarily observed on cell surfaces (42,79), some studies also described ACE2 granular localization in other cell types of epithelial origin (9,80). A similar intracellular localization and putative trafficking were observed for the viral receptor CAR-SIV (78), also expected to be mainly localized on the cell membrane.…”

ACE2: The Major Cell Entry Receptor for SARS-CoV-2

“…Whether there is upregulation of ACE2 expression in smokers that could increase their sensitivity to infection is still a matter of debate. In the literature, there are reports supporting [31][32][33] and refuting [34][35][36] this hypothesis.…”

“…Since the beginning of the COVID-19 pandemic, hypertension and diabetes have been correlated with higher risk of mortality, and initial reports speculated that angiotensin converting enzyme inhibitors (ACEi) and angiotensin receptor blockers (ARBs), which are commonly used therapeutic agents for these conditions, would up-regulate ACE2 expression, thus increasing the risk of severe illness [37]. Recent evidence has challenged this hypothesis, demonstrating both mechanistically and in large cohort studies that ACEi and ARBs do not up-regulate ACE2 and are not associated with an increased mortality [35,36].…”

Ciliary Dysfunction Secondary to COVID-19. Explanation of the Pathogenesis From Analysis of Human Interactome With Sars-Cov-2 Proteome

“…While there are still no studies of the link between CD147 expression in respiratory ciliary epithelium with SARS-CoV-2 infection, at least it is known that ACE2 receptor protein robustly localizes within the motile cilia of airway epithelial cells, which likely represents the initial or early subcellular site of SARS-CoV-2 viral entry during host respiratory transmission [18] . Although the overall intensity of ACE2 expression in the lung is low compared to the kidney, testis, and intestinal villi [18] , we know that the SARS-CoV-2 could infect the lung via the CD147-Cyclophilin A-SARS-CoV-2 N route of infection [1] .…”