SARS-CoV-2 Receptor ACE2 Is an Interferon-Stimulated Gene in Human Airway Epithelial Cells and Is Detected in Specific Cell Subsets across Tissues

Recently, the SARS-CoV-2 induced disease COVID-19 has spread all over the world. Nearly 20% of the patients have severe or critical conditions. SARS-CoV-2 exploits ACE2 for host cell entry. ACE2 plays an essential role in the renin-angiotensin-aldosterone system (RAAS), which regulates blood pressure and fluid balance. ACE2 also protects organs from inflammatory injuries and regulates intestinal functions. ACE2 can be shed by two proteases, ADAM17 and TMPRSS2. TMPRSS2-cleaved ACE2 allows SARS-CoV-2 cell entry, whereas ADAM17-cleaved ACE2 offers protection to organs. SARS-CoV-2 infection-caused ACE2 dysfunction worsens COVID-19 and could initiate multi-organ failure. Here, we will explain the role of ACE2 in the pathogenesis of severe and critical conditions of COVID-19 and discuss auspicious strategies for controlling the disease.Viruses 2020, 12, 491 2 of 10 Profile of ACE2Human angiotensin-converting enzyme-related carboxypeptidase ACE2 is encoded by the ACE2 gene which maps to chromosome Xp22 [6]. ACE2 is a type I transmembrane protein, comprised of an extracellular heavily N-glycosylated N-terminal domain containing the carboxypeptidase site and a short intracellular C-terminal cytoplasmic tail [7]. The N-terminal peptidase domain is also the SARS-CoV binding site [8]. There are two forms of ACE2 protein: cellular (membrane-bound) form and circulating (soluble) form. Cellular ACE2 protein is the full-length protein which is expressed abundantly in pneumocytes and enterocytes of the small intestine [9]. ACE2 is also expressed in vascular endothelial cells of the heart, the kidneys, and other organs, such as the brain. However, ACE2 is absent in the spleen, thymus, lymph nodes, bone marrow, and cells of the immune system (including B and T lymphocytes, and macrophages) [10,11].Circulating ACE2 (with the N-terminal peptidase domain) is cleaved from the full-length ACE2 on the cell membrane by the metalloprotease ADAM17 and then released into the extracellular environment [7]. The type II transmembrane serine protease, TMPRSS2 was found to compete with ADAM17 for ACE2 shedding but cleaves ACE2 differently. Both ADAM17 and TMPRSS2 remove a short C-terminal fragment from ACE2. Arginine and lysine residues within amino acids 652 to 659 are critical for ADAM17 shedding, whereas arginine and lysine residues within amino acids 697 to 716 are essential for TMPRSS2 shedding. Only cleavage by TMPRSS2 results in augmented SARS-CoV cell entry [12][13][14][15]. There are two ways for SARS-CoV to enter the target cell: endocytosis, and fusion of the viral membrane with a membrane of the target cell, which is 100 times more efficient than endocytosis for viral replication [16]. With the help of TMPRSS2, ADAM17-regulated ectodomain shedding of ACE2 could induce SARS-CoV cell entry through endocytosis [7,12]; however, ADAM17 activity is not required for SARS-CoV cell entry through fusion [12]. As the N-terminal domain is the coronavirus binding site, circulating ACE2 also binds to the virus. Iwata-Yoshikawa et al. infected both ...

Coronavirus disease 19 is caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and currently has detrimental human health, community and economic impacts around the world. In SARS-CoV-2-infected lung, induction of immune cell-recruiting cytokines is initially poor.When induction does occur, this may in fact exacerbate infection. These observations suggest that baseline levels of leukocytes, already residing in the lung prior to infection, may be important for orchestrating an effective early immune response. Hence, we performed "in silico flow cytometry" on 1,927 human lung tissues to deconvolute the levels of seven leukocyte types involved in triggering an acute anti-viral cellular immune response. Baseline levels of CD8+ T cells, resting natural killer (NK) cells and activated NK cells are significantly lower in lung tissues with high expression of the SARS-CoV-2 host cell entry receptor ACE2. We observe this in univariate analyses, in multivariate analyses that include sex, age, race, body mass index and smoking history, and in two independent datasets. Elevated ACE2 expression increases sensitivity to coronavirus infection. Thus, our results suggest that a subgroup of individuals may be exceedingly susceptible to COVID-19 due to concomitant high preexisting ACE2 expression and low baseline cytotoxic lymphocyte levels in the lung.

Coronavirus disease 2019 (COVID-19) has disproportionately affected certain vulnerable populations. Studies noted higher rates of certain comorbidities such as hypertension, diabetes mellitus, and chronic obstructive pulmonary disease in patients infected with COVID-19 with severe disease. 1 Additionally, areas with more racial/ethnic minorities and higher rates of poverty have been shown to have higher rates of COVID-19 hospitalization and death. 2 After adjustment for comorbidities, age has been independently associated with increased mortality due to COVID-19. 3 However, limited attention has been given to children, who appear to have lower risk of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection and mortality.In this issue of JAMA, Bunyavanich et al 4 identify a possible factor that may be related to lower rates of SARS-CoV-2 infection in children. The authors evaluated gene expression in nasal epithelial samples collected as part of a study involving patients with asthma from 2015 to 2018. The nasal epithelium is one of the first sites of infection with SARS-CoV-2, and the investigators probed for the expression of the cell surface enzyme angiotensin-converting enzyme 2 (ACE2), which has been proven to bind to SARS-CoV-2 spike protein and promote internalization of the virus into human cells. 5 Among a cohort of 305 patients aged 4 to 60 years, older children (10-17 years old; n = 185), young adults (18-24 years old; n = 46), and adults (≥25 years old; n = 29) all had higher expression of ACE2 in the nasal epithelium compared with younger children (4-9 years old; n = 45), and ACE2 expression was higher with each subsequent age group after adjusting for sex and asthma.Numerous studies have highlighted the low rates of SARS-CoV-2 infection in children compared with adults. Children have been shown to have fewer and less severe symptoms compared with adults. 6,7 This leads to the question of whether low rates of SARS-CoV-2 infection in children are due to low rates of testing in children, or if children are less susceptible to infection. An evaluation of 1286 close contacts of index cases in China found that infection rates in children were comparable with or slightly higher than in younger adults (aged 30-49 years) but were significantly lower than in older patients (aged ≥60 years). 8 This finding suggests that children seem to have similar rates of becoming infected compared with middle-aged adults following close contact with a person infected with SARS-CoV-2. In contrast, a targeted screening approach in Iceland found SARS-CoV-2 in 6.7% of children younger than 10 years old (n = 564) compared with in 13.7% of people aged 10 years or older (n = 8635). A population-wide screening approach not