key: cord-0768502-oqu326r4
authors: Yao, Yin; Wang, Hai; Liu, Zheng
title: Expression of ACE2 in airways: Implication for COVID‐19 risk and disease management in patients with chronic inflammatory respiratory diseases
date: 2020-10-06
journal: Clin Exp Allergy
DOI: 10.1111/cea.13746
sha: d66e8368131c1f8493b54fdc92f908304cefa508
doc_id: 768502
cord_uid: oqu326r4

Coronavirus disease 2019 (COVID‐19), caused by the novel severe acute respiratory syndrome coronavirus 2 (SARS‐CoV‐2), has been a rising international cause of morbidity and mortality. Angiotensin‐converting enzyme 2 (ACE2) is identified as a key cell entry receptor for SARS‐CoV‐2 and suggested to be a limiting factor for viral entry at the initial infection stage. Recent studies have demonstrated that ACE2 expression is highly enriched in nasal epithelial cells and type II alveolar epithelial cells, highlighting the importance of respiratory tract as the primary target site of SARS‐CoV‐2. The expression of ACE2 in airway epithelial cells is tightly regulated by inflammatory milieu and environmental and internal stimuli. Very recently, ACE2 has been reported to have different expression levels in airways under distinct chronic inflammatory airway diseases, such as chronic obstructive pulmonary disease (COPD) and allergic asthma, which may associate with the COVID‐19 risk and affect the management of primary airway diseases. In this review, we focus on the cutting‐edge progress in distribution, expression, and regulation of ACE2 in respiratory system in physiological and pathological conditions, and their implication for the development of COVID‐19. We also discuss the management of airway diseases, including asthma, COPD, allergic rhinitis, and rhinosinusitis in the era of COVID‐19.

diabetes, cardiovascular disease, and chronic obstructive pulmonary disease (COPD) as the risk factors for COVID-19 (Table 1) , associated with severe illness and death. [12] [13] [14] [15] [16] [17] [18] [19] [20] [21] [22] [23] [24] [25] [26] [27] [28] [29] [30] However, the mechanisms underpinning the contribution of these factors for the development of COVID-19 are not fully understood, which may be associated with the capacity of SARS-CoV-2 to invade host cells and infect an individual person under different conditions. Severe acute respiratory syndrome coronavirus 2 belongs to the broad family of viruses known as coronaviruses and shares 79.6% sequence identity to SARS-CoV, the virus accounting for SARS pandemic in 2003. [31] [32] [33] Similar to SARS-CoV, SARS-CoV-2 has been discovered to enter cells via binding to angiotensin-converting enzyme 2 (ACE2). 32, [34] [35] [36] The SARS-CoV-2 spike protein demonstrates at least 10 times higher affinity in binding ACE2 than does SARS-CoV. 37 High ACE2 expression on host cells increases the susceptibility to SARS-CoV-2, and blocking ACE2 signalling prevents the viral infection in vitro. 32, 36, 38 In humans, ACE2 expression has been found to be increased in the lung of smokers and patients with COPD, and those patients have been reported more likely to have severe COVID-19, implicating a central role of ACE2 in COVID-19 development. 13, 19, 39 Respiratory tract is continuously exposed to a multitude of pollutants and inhaled pathogens, making them a primary target of SARS-CoV-2. It is supported by the recent discovery of enriched ACE2 expression in nasal epithelial cells and type II alveolar (AT2) cells. [40] [41] [42] Airway diseases, including allergic rhinitis (AR), sinusitis, asthma, and COPD, are highly prevalent world-wide, affecting up to 50% of the populations. [43] [44] [45] The current COVID-19 pandemic makes the interaction between primary inflammatory airway diseases and COVID-19 critical for mitigating COVID-19 risk and management of primary airway diseases. Do patients with inflammatory airway diseases have an altered susceptibility to COVID-19? Will those patients have a unique disease course if infected by SARS-CoV-2? Will COVID-19 affect the management of the primary airway diseases? Understanding the expression and function of ACE2 in airways in physiological and pathological conditions may give valuable hints to answer these questions. In this review, we summarized cutting-edge advances in the very fast-moving

Comorbidities field of ACE2 study and highlighted the changes in ACE2 expression and its implication for COVID-19 risk and disease management in patients with common upper and lower inflammatory airway diseases, including AR, rhinosinusitis, asthma, and COPD.

The 40 kb ACE2 gene located on chromosome Xp22 was first described in 2000. 46, 47 The encoded human ACE2 protein is a type I transmembrane glycoprotein, which consists of 805 amino acids. 46, 47 ACE2 orientates outside with the N-terminus and anchors to the plasma membrane through a short intracellular C-terminal tail. [46] [47] [48] The highly conserved catalytic site of ACE2 faces the extracellular space, where it can metabolize circulating peptides. 46 Figure 1 ) and a single residue from Ang I to yield Ang (1-9), whereas, as the peptidyl dipeptidase, ACE cleaves the decapeptide Ang I into an octapeptide Ang II. 49 Ang II is the key player in renin-angiotensin system (RAS), a hormone system that maintains blood pressure homeostasis and fluid and salt balance. 50 Ang II mediates vasoconstriction and thus contributes to the overactivation of RAS, which is associated with a spectrum of diseases including hypertension, heart failure, and renal disease. 50, 51 Therefore, ACE2 plays a crucial role in maintaining the balance of RAS by countering the activities of Ang II. Furthermore, ACE2 also can convert Ang A into alamandine, a protector in the cardiovascular system. 49 The membrane-bound ACE2 can be cleaved by a disintegrin and metalloproteinase 17 to become the soluble form, which may function as a competitive interceptor of binding ligands of membrane ACE2. 52

In lung, Ang II is able to induce bronchoconstriction, vasoconstriction, fibroproliferation, cytokine expression, and cell apoptosis, thus promoting tissue injury. 49 As a negative regulator of Ang II, ACE2

has been reported to protect the lung from injury ( Figure 1 ). 49 In the acute lung injury/acute respiratory distress syndrome model, the lack F I G U R E 1 Expression and role of angiotensin-converting enzyme 2 (ACE2) in airways. ACE2 is expressed in airways, with a particularly higher expression level in nasal epithelial cells and type II alveolar epithelial cells in the lung. Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) binds to ACE2 expressed on human airway epithelial cells, and then, the serine protease TMPRSS2 cleaves and activates the spike protein of SARS-CoV-2, which ultimately facilities virus-cell fusion and cell entry. As a peptidase, ACE2 catalyses and inactivates angiotensin (Ang) II and produces the vasodilator peptide Ang (1-7). Ang II induces bronchoconstriction, vasoconstriction, fibroproliferation, cytokine expression, and cell apoptosis, thus promoting tissue injury. Accordingly, ACE2 has protective effects against tissue injury, including acute lung injury (ALI), acute respiratory distress syndrome (ARDS), fibrosis, chronic obstructive pulmonary disease (COPD), and allergic asthma of ACE2 expression in the lung resulted in exaggerated lung oedema, massive neutrophil accumulation, and deteriorated lung function. 53 Vice versa, treatment with recombinant ACE2 protein protected mice from severe acute lung injury. 53 Transforming growth factor (TGF)-β1

is the most potent profibrotic cytokine and may act downstream of Ang II. 54 ACE2 overexpression significantly reduced TGF-β1 levels and demonstrated a protective effect against the development of bleomycin-induced fibrosis in murine models. 55 In the murine COPD model induced by cigarette smoking exposure, ACE2 overexpression in the lung significantly improved the lung function and pathological abnormalities. 56 In an ovalbumin-challenged mouse model of asthma, Ang (1-7) modulated ovalbumin-induced increases in total cell counts, eosinophils, and lymphocytes, and decreased goblet cell hyper/metaplasia. 57 These results support an important role of Ang (1-7) and ACE2 in reducing airway allergic inflammation ( Figure 1 ). 57

Besides as a peptidase to catalyse Ang II cleavage in the physiological condition, ACE2 has been identified as a functional receptor for the SARS-CoV and is important for the disease development after SARS-CoV infection. 31,53,58 ACE2 purified from Vero E6 cells was able to bind the S1 domain of the SARS-CoV spike protein in vitro. 31 ACE2 knockout mice showed reduced viral replication in the lungs in SARS-CoV infection. 59 In contrast, transgenic mice expressing human ACE2 were highly susceptible to SARS-CoV infection with more severe pulmonary lesions. 60 In addition, anti-ACE2 antibody and soluble ACE2 treatment inhibited SARS-CoV infection in mice. 58 Full-length genome sequencing revealed that SARS-CoV-2 shares 79.6% sequence identity to SARS-CoV. 32 SARS-CoV-2 has been found employing the same receptor as SARS-CoV, ACE2, for host cell entry ( Figure 1 ). 32, 34, 35 To invade the host cells, there is a need for another player, the transmembrane protease TMPRSS2, a cellular serine protease, which cleaves and activates the SARS-CoV-2 spike protein and facilitates human cell entry. 38 The spike protein of SARS-CoV-2 also contains a furin-like cleavage site, 61-63 suggesting a potential role of furin and furin-like proteases in SARS-CoV-2 cell entry.

Wrapp et al described a 3.5-angstrom-resolution structure of the SARS-CoV-2 trimeric spike protein by cryo-electron microscopy and found that SARS-CoV-2 spike protein binds to ACE2 at least 10 times more tightly than that of SARS-CoV, 37 

Nasal cavity is the primary site of exposure to pollutants, airborne allergens, and inhaled pathogens and acts as the gateway to res- Notably, TMPRSS2 was found having a broader expression (28%) than ACE2 (4%) in nasal epithelial cells characterized by secretory phenotype, 41 suggesting that ACE2 may be the limiting factor for viral entry. In addition, TMPRSS2 is only expressed in a subset of ACE2-positive cells. 40 Thus, SARS-CoV-2 may use alternative facilitating mechanism to entry host cells. A potential substitute for TMPRSS2 is cathepsin B, another protease, which was found to be expressed in more than 70% of ACE2-positive cells. 40 ACE2 gene has been found to be coexpressed with genes involved in innate immunity in nasal epithelial cells, highlighting the important role of nasal epithelial cells in respiratory viral infection, spread and clearance. 40, 41 In contrast, no significant ACE2 gene expression in immune cell populations, including T cells, dendritic cells, and mast cells, was discovered in nasal mucosal tissues. 40, 41 Anosmia is typical of viral rhinitis, and smell and taste disorder has been reported as one of the common symptoms of COVID-19

patients, [68] [69] [70] raising the possibility that SARS-CoV-2 may infect olfactory epithelium or sensory neurons. Indeed, high expression of ACE2

in epithelial cells of tongue has been reported based on the bulk and single-cell RNA sequencing of oral tissues. 71 Expression of ACE2 and TMPRSS2 was also detected in human and murine olfactory epithelium. 72 41, 73 The expression pattern of ACE2 protein in human olfactory epithelium was verified by immunohistochemical staining of biopsied tissues (preprint). 73 These data indicate that SARS-CoV-2 infection of support cells in olfactory epithelium and olfactory bulb may disrupt the structure of olfactory epithelium and impair the function of olfactory sensory neurons or bulb neurons, ultimately resulting the disturbance in smell perception in COVID-19 patients.

The lung is the most important target organ of SARS-CoV-2 infection.

An analysis of single-cell RNA sequencing data derived from normal human lung tissues revealed that ACE2 gene was expressed by 0.64% of cells in lung and 83% of ACE2-expressing cells were AT2 cells and 5% were type I alveolar cells (AT1) (Figure 1 ). 75 Nevertheless, bronchial airway epithelial cells, fibroblasts, endothelial cells, and macrophages had low expression of ACE2. 75 Consistently, the expression of ACE2 in AT2, AT1, and ciliated cells was revealed by other studies in single-cell level. 40, 41, [76] [77] [78] [79] In line with the single-cell RNA sequencing finding, by immunohistochemistry study, Bezara et al found that about 1% of surfactant protein C-positive AT2 cells were positive for ACE2 protein expression, whereas alveolar macrophages were negative for ACE2 staining (preprint). 80 Through investigating ACE2 protein expression in different anatomical regions, they found that apical ACE2 expression was rare and limited to ciliated cells in the trachea and bronchi (preprint). 80 In the submucosal glands of large airways, occasional serous cells and vessels near the acini were positive for ACE2, but ACE2 was regionally localized in ciliated cells in bronchioles (preprint). 80 Notably, regional distribution of ACE2 protein varied across different donors (preprint), 80 and cellular models will be required for assessing therapeutic interventions targeting the IFN system when studying ACE2-associated biology.

Recently, several studies reported that IL-13 down-regulated ACE2 mRNA expression in human nasal and bronchial epithelial cells cultured with an air-liquid interface method ( Figure 2) . 42, 84, 85 However,

Ziegler et al showed that IL-4 and IL-13 had no effect on ACE2 mRNA expression in human nasal basal epithelial cells when cultured submerged. 41 It also should be noted that the data regarding the regulation of ACE2 expression at protein level are still lacking.

Allergen challenge can initiate and perpetuate airway type 2 (T2) inflammation. 86 Jackson et al have found that allergic sensitization was inversely related to ACE2 mRNA expression in nasal epithelium in asthmatic children. 84 In addition, significant negative correlations between ACE2 mRNA expression and T2 biomarkers including the number of positive allergen-specific immunoglobulin (Ig)E tests, total IgE, fractional exhaled nitric oxide, and nasal epithelial IL-13 expression were found by them, although most correlation coefficients were low. 84 Furthermore, Jackson et al found that nasal cat allergen led to a significant reduction in ACE2 mRNA expression in nasal brush samples in adult AR patients allergic to cat. 84 Consistently, segmental allergen bronchoprovocation to dust mite, ragweed, or cat significantly reduced ACE2 mRNA expression in bronchial brushing cells in adult patients with mild asthma. 84 Therefore, respiratory allergen exposures and T2 inflammation decrease ACE2 expression in both upper and lower airways ( Figure 2) .

Although eosinophilia is a hallmark of allergic respiratory inflammation, 87 accumulating evidence indicates an antiviral activity of eosinophils. 87 Eosinopenia has been noted in patients with COVID-19. 7,88 Patients with fewer peripheral blood eosinophils displayed worse radiographic aggravation and longer course of disease compared to those with normal eosinophil counts. 88 Peripheral blood eosinophil levels have been reported to be gradually increased in recovered patients before discharge, accompanied by the improved clinical status. 88 These data suggest that peripheral blood eosinophil count may be an indicator for diagnosis, clinical status monitor, and outcome prediction of COVID-19. higher circulating total T cell counts than those without allergy. 90 However, the relationship between allergy and COVID-19 obviously needs to be evaluated and validated in larger cohorts and those with different genetic and socio-economic backgrounds.

Several epidemiological studies reported that cigarette smoking exposure associated with increased risk for COVID-19 and current and former smokers was likely to develop severe COVID-19 than never smokers. 3, 13, 91, 92 By comprehensively analysing transcriptomic and microarray data sets, Cai et al found a markedly higher ACE2 mRNA F I G U R E 2 Regulation of angiotensinconverting enzyme 2 (ACE2) expression in airway epithelial cells. Tobacco exposure promotes ACE2 expression in airway epithelial cells, which may associate with increased ACE2 expression in the lung of patients with chronic obstructive pulmonary disease (COPD). Interferon (IFN)-α and IFN-γ promote ACE2 expression in airway epithelial cells. Allergens and interleukin (IL)-13 inhibit ACE2 expression in airway epithelial cells, may account for the lower ACE2 expression in patients with allergic asthma. Varied ACE2 in distinct chronic inflammatory airway diseases may contribute to different susceptibilities to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection expression in ever smokers compared with never smokers in both airway epithelial cells and lung tissues in COPD and non-COPD subjects. 19 Brake et al observed an enhanced ACE2 protein expression in resected lung tissues from smokers with COPD and smokers with normal lung function when compared to heathy non-smoking individuals, with more prominent increase in smokers with COPD compared with smokers with normal lung function. 93 Leung et al found that current smokers had a significantly higher ACE2 mRNA expression in bronchial bushing cells than never smoker. 39 In addition, smoking status defined by never, former, and current smokers was significantly associated with ACE2 gene expression in large airway epithelium and lung tissues. 19 Therefore, these consistent results strongly support that tobacco exposure significant up-regulates ACE2 gene expression in airways ( Figure 2) . However, further studies are needed to explore the mechanisms underlying tobacco-induced up-regulation of ACE2 pulmonary expression. In addition, electronic cigarette consumption has significantly increased, whether electronic cigarettes have effects on ACE2 expression remains to be determined.

Intranasal and inhaled corticosteroids serve as the cornerstone for the treatment of inflammatory airway disorders such as AR, chronic rhinosinusitis (CRS), COPD, and asthma. 45 98 Obviously, more studies are needed to clarify the impact of biologics on COVID-19 in patients with chronic inflammatory airway diseases.

A number of studies demonstrated a lower risk of SARS-CoV-2 infection in children compared with adults. 99 Older age has been independently associated with increased mortality of COVID-19 after adjusting for comorbidities (Table 1) (Table 1) , 2,12,13,15 suggesting a gender-related expression of ACE2.

Indeed, as an X chromosome-encoded gene, renal ACE2 expression has been reported to be significantly down-regulated by oestrogens. 101 In addition to the direct effect on ACE2 expression, sex hormone may also modify the immune response to viral infection. For examples, plasmacytoid dendritic cells from adult females produced more IFN-α than those from adult males in response to virus infection. 102 In addition, emerging evidence has implicated an association between ethnicity and incidence or outcome of COVID-19. By Asian people were at a higher risk of death compared with people with White ethnicity. 12 In addition, Black and minority ethnicity people have been found to be associated with increased SARS-CoV-2 infection and poor clinical outcome. 23, 24 The causes for ethnic disparities for COVID-19 development are unclear and may be related to different socio-economic and cultural background, lifestyle, genetic predisposition, and ACE2 expression. 

Although asthmatic patients are at risk of more severe outcome after common cold virus infection than people without asthma, 109 asthma has unexpectedly not been identified as a significant risk factor for severe 7, 110 Low prevalence of asthma (0%-0.9%) was observed in patients with COVID-19 in several studies in China. 13, 16, 91, 111 In a US cohort including 1526 patients with COVID-19, Chhiba et al recorded a relative high prevalence of asthma (14%); however, there was no significant difference in hospitalization rate or mortality between patients with and without asthma. 108 Notably, asthma is a heterogeneous disease with varying levels of severity and distinct endotypes. In a large cohort (17 278 392 adults) study in the UK, severe asthma (with oral steroid treatment) was identified as a risk factor associated with COVID-19 death. 12 Allergic asthma is the most common type of asthma triggered by inhaled allergens. scores of T2 gene expression. 89 These data suggest an association between asthma endotypes and COVID-19, which was supported by the finding that T2-low asthmatic patients demonstrated characteristics corresponding to risk factors for severe COVID-19, including male sex and history of hypertension. 89 Taken together, although allergic asthma appears to be a protective factor for COVID-19

( Figure 2) , the associations between different phenotypic and endotypic asthma and COVID-19 remain to be defined.

Among the airway inflammatory diseases, COPD is the most commonly reported comorbidity in COVID-19 patients and the prevalence ranged from 1.5% to 5%. 13, 91, 112 Previous epidemiological studies have associated the COPD comorbidity with the severe illness and fatalities in COVID-19 patients. 13, 20 Guan et al reported that severe COVID-19 cases had higher frequencies of COPD comorbidity than non-severe cases. 13 Leung et al reported that ACE2

protein expression in the bronchial epithelial cells was significantly increased in COPD versus non-COPD subjects. 39 Smoking is the primary aetiological factor for COPD, and evidence has shown increased ACE2 mRNA expression in smokers than in non-smokers. 19 Interestingly, Leung et al found that ACE2 expression was still increased in bronchial epithelial cells in COPD than in non-COPD subjects after adjusting the smoking status. 39 Therefore, it is likely that additional factors beyond smoking can modulate ACE2 expression in COPD patients. tients with asthma to continue to use their maintenance medications even during the pandemic. 116 In addition, balancing the risk of losing disease control and the lack of evidence or expectation of increased infectivity or mortality, ACAAI and AAAAI recommend to continue administration of biologic agents. 116 The Global

Initiative for Chronic Obstructive Lung Disease also advises that COPD patients should maintain their regular therapy, including corticosteroid administration, during the COVID-19 pandemic. 117 Collectively, although glucocorticoids and biologics targeting T2 inflammation may modify the ACE2 expression in airways, there is no direct evidence that they will change the risk for COVID-19.

Considering the risk of exacerbation of primary airway diseases after stopping baseline treatment and subsequently increased potential risk to COVID-19, the baseline treatments are suggested to be continued for patients with chronic inflammatory airway disorders.

Cardiovascular diseases including hypertension and heart failure are the leading causes of death globally. 118 Antivirus drugs such as chloroquine, hydroxychloroquine, remdesivir, and lopinavir have been recommended for the treatment of COVID-19, although none of them has been thoroughly proved by randomized controlled trials. 11, 125 There are big controversies regarding their therapeutic effects on COVID-19. Since ACE2 is likely an IFN-stimulated gene and may be induced by viral infection, 41 antiviral treatment may reduce the ACE2 expression in airways in patients with COVID-19. Of note, as the Ang II converting enzyme, ACE2 protects lung from a variety of injuries. 49 The approaches targeting ACE2

for treating COVID-19 should be carefully considered in relation to the protective role of ACE2 in lung physiology and pathology. 

The authors declare no conflict of interests.

All authors participated in drafting and writing the manuscript and approved the manuscript.

Data sharing is not applicable to this article as no new data were created or analysed in this study.

https://orcid.org/0000-0002-4168-6702

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