ACE2: Entry Receptor for SARS-CoV-2

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ACE2: Entry Receptor for SARS-CoV-2 May 1, 2020 22:07:29 GMT

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Post by Admin on May 1, 2020 22:07:29 GMT

ACE2 and acute lung injury
Experimental SARS-CoV infection induces acute respiratory failure and lung parenchymal injury characterized by alveolar wall thickening, pulmonary vascular hyperpermeability, and inflammatory cell infiltration in mice [27]. After SARS-CoV infection in mice, lung ACE2 protein levels are greatly reduced, while ACE levels are not changed [27]. These findings are consistent with the previous observation that coronaviruses specifically downregulate ACE2 expression in host cells, depending on virus replication [29]. In addition, SARS-CoV-induced acute lung injury is remarkably attenuated in ACE2 knockout mice compared with wild-type mice [27]. Lung angiotensin II levels increase in wild-type mice after SARS-CoV infection [27]. Acid aspiration mice, an ARDS model, show functional and pathological changes mimicking SARS-CoV-induced lung injury [30]. The lung angiotensin II levels increase after acid aspiration, and SARS-CoV-S protein treatment elicits a further angiotensin II increase [27]. Interestingly, exogenous recombinant ACE2 treatment rescues acid aspiration-induced acute lung injury [30]. Taking this evidence together, the following hypothesis has been raised for the mechanism underlying SARS-CoV-induced lung injury: SARS-CoV infection downregulates lung ACE2 and in turn, shifts the balance toward the dominance of the ACE/angiotensin II/AT1R system over the ACE2/angiotensin 1-7/mas receptor system in the lung. As a result, noncompeting angiotensin II accumulation occurs, resulting in acute lung injury through AT1R activation [27].

It should be noted that a similar mechanism is proposed for the severe lung injury caused by the avian influenza A virus H5N1, which has spread worldwide in humans with a high mortality rate. After H5N1 virus infection in mice, lung ACE2 expression is downregulated, and serum angiotensin II levels increase [31]. Acute lung injury is augmented by ACE2 knockout in H5N1-infected mice, while the administration of recombinant human ACE2 ameliorates H5N1-induced lung injury in mice [31]. Moreover, in other mouse models of acute lung injury/ARDS, such as acid aspiration, sepsis, and drug-induced lung fibrosis, it has been shown that ACE2 expression is downregulated in response to noxious stimuli and that acute lung injury is aggravated by ACE2 knockout and rescued by exogenous ACE2 administration or AT1R knockout [30, 32]. Accordingly, it is suggested that the angiotensin II/AT1R-induced aggravation resulting from ACE2 downregulation and the protective effects of ACE2 are not specific to lung injury in SARS but rather may be common to acute lung injury/ARDS induced by various viral infections and lung diseases.

Effects of RAS inhibitors on ACE2 and SARS-CoV-induced lung injury
Several kinds of ARBs (e.g., olmesartan, telmisartan, losartan, and azilsartan) have been shown to increase the mRNA or protein levels of ACE2 in animal models of heart diseases (hypertensive hypertrophy, autoimmune myocarditis, dilated cardiomyopathy, myocardial infarction, and diabetic cardiomyopathy) [8,9,10,11,12,13,14] and chronic kidney disease (hypertensive nephropathy and diabetic nephropathy) [15, 16], as well as normal rat heart and renal vasculature [17, 18] and hypertensive rat aorta (but not the carotid artery) [19, 20]. ACEI does not inhibit ACE2 as a pharmacological property. In normal rats, lisinopril has been shown to modestly increase cardiac ACE2 mRNA levels while not changing cardiac ACE2 activity [17]. In the myocardial infarction model, valsartan, ramipril, and their combination have no effects on cardiac ACE2 expression [33]. It should be noted that the doses of ARBs and ACEIs used in these animal studies were much greater than those in clinical practice so that the observed effects of these drugs on ACE2 expression and activity could not be extrapolated to clinical situations in humans. Importantly, no clinical data exist regarding the effects of ARBs and ACEIs on human tissue ACE2 expression or activity in vivo. Although there are several clinical studies investigating the changes in plasma or urine levels of the soluble form of ACE2 in hypertension and CVD patients receiving ARBs or ACEIs, the soluble form of ACE2 in the plasma and urine is not a reliable indicator of the activity of tissue ACE2, namely, membrane-bound ACE2 [22]. Importantly, there are no data on the effects of ARBs and ACEIs on lung ACE2 expression either in animal models or humans. It is still unknown whether the changes in ACE2 levels (for example, ARB-induced upregulation) actually facilitate greater engagement and entry of SARS-CoV and other viruses, even in animal models.

On the other hand, it has been shown that pretreatment with losartan, an ARB, ameliorates acute pulmonary edema and lung injury in SARS-CoV-S protein-treated mice after acid aspiration (Fig. 2) [27]. Taken together with the lung angiotensin II level elevation [27], this evidence suggested that even after considering the speculation that viral load would be enhanced by ACE2 upregulation, the net effects of ARBs would be favorable to prevent SARS-CoV-induced acute lung injury in this model. In addition, there is another possibility that the ARB pretreatment-induced baseline ACE2 increase prior to SARS-CoV infection would result in higher ACE2 levels that remained after SARS-CoV-induced downregulation and consequently conferred protection against lung injury in this model [22, 34]. However, in interpreting the results of this study, it should be noted that the effects of losartan have been observed merely in mice treated with SARS-CoV-S protein in addition to acid aspiration but not in mice treated with SARS-CoV-S protein alone. Additionally, data on lung ACE2 levels before and after treatment with SARS-CoV-S protein and acid aspiration are lacking in mice pretreated with or without losartan.

Fig. 2

Current evidence in COVID-19
Earlier studies reported that the case fatality rate was high in COVID-19 patients with comorbidities such as older age, hypertension, diabetes mellitus, CVD, chronic pulmonary disease, and malignancy [3, 4]. Because patients with hypertension and CVD are likely treated with ACEIs or ARBs, the concern is raised regarding whether the use of ACEIs and ARBs may aggravate the morbidity and mortality of COVID-19 [21]. However, it was possible that the observed phenomenon would result from reverse causality because older patients are at the highest risk for COVID-19 and concurrently tend to have multiple comorbidities, including hypertension and CVD, and because adjustments for age and other possible confounding factors were not performed in such earlier studies [22, 35, 36]. Indeed, in a recent retrospective, multicenter cohort study enrolling 191 confirmed COVID-19 patients in Wuhan, China, multivariable regression analysis revealed that independent risk factors for in-hospital death are older age, higher Sequential Organ Failure Assessment score, and higher D-dimer levels at the early stage of COVID-19, although hypertension, diabetes, and coronary artery disease were not included [37].

A small case study reported that plasma angiotensin II levels were markedly elevated and linearly associated with viral load and lung injury severity in COVID-19 pneumonia patients [38]. Given that a remarkable elevation of circulating levels was also documented in various kinds of cytokines (IL-6, IL-10, TNF-alpha, etc.), it is unknown whether these findings of angiotensin II are the cause or result of a systemic cytokine storm in COVID-19 patients [39]. In the context of the effects of ARBs and AECIs, a retrospective, single-center analysis enrolling 112 COVID-19 patients showed that the use of ARBs and ACEIs had no effects on the morbidity and mortality of COVID-19 patients with CVD [40]. Currently, a case-control study is underway to clarify the effects of ACEIs and ARBs on the severity of COVID-19 in Italy (NCT04318418). Most importantly, at present, there is no large-scale study with convincing evidence to determine whether ARBs and ACEIs play a neutral, beneficial, or harmful role in the susceptibility to SARS-CoV-2 and the severity and outcomes of COVID-19 patients [22, 34,35,36, 41].

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ACE2: Entry Receptor for SARS-CoV-2 May 2, 2020 5:29:17 GMT

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Post by Admin on May 2, 2020 5:29:17 GMT

Potential therapies targeting ACE2 and angiotensin II
In addition to vaccine development and antiviral agents, the modulation of the RAS, especially by ACE2 and angiotensin II, is highlighted as a potential therapeutic target for COVID-19. Based on an animal study suggesting the beneficial net effects of ARB in SARS-CoV-infected acute lung injury mice [27], multicenter, double-blinded placebo-controlled, randomized trials (RCTs) are currently being conducted to investigate the effects of losartan on mortality and hospital admission in COVID-19 patients requiring hospital admission (NCT04312009) and not requiring hospital admission (NCT04311177), respectively.

Recombinant ACE2 is another candidate to prevent COVID-19 pneumonia. As described above, the efficacy of exogenous recombinant ACE2 has been shown in animal models of acute lung injury/ARDS [30, 31]. It is also possible that the circulating soluble form of ACE2 may act as a decoy receptor that binds to SARS-CoV-2 and competitively inhibits virus entry to host target cells mediated by membrane-bound ACE2. To investigate the efficacy of human recombinant ACE2 in the treatment of COVID-19 patients, a randomized, controlled, pilot clinical study was planned (NCT04287686). However, this study was withdrawn on March 17, 2020.

TMPRSS2 is a membrane protease for ACE2 priming, which is a crucial step for the fusion of SARS-CoV-2 and target cell membranes and the resultant viral entry into the cells [6]. Nafamostat mesylate and camostat mesylate are TMPRSS2 inhibitors that have been used for the treatment of acute pancreatitis in Japan. Currently, a clinical trial evaluating the efficacy of nafamostat and camostat for treating COVID-19 is underway in Japan (https://www.u-tokyo.ac.jp/focus/en/articles/z0508_00083.html).

Risk limits of RAS inhibitor therapy in the COVID-19 pandemic
The concern regarding whether ARBs and ACEIs may have harmful effects on the morbidity and mortality of COVID-19 patients is based on the speculation that these drugs would upregulate ACE2, a receptor for SARS-CoV-2, which would increase the viral load and then augment lung injury. However, the evidence of ACE2 upregulation is limited only in animal studies using the relatively high (namely, pharmacological) doses of several ARBs and one ACEI. Additionally, it remains unclear whether the ARB/ACE-induced ACE2 increase actually enhances the susceptibility to SARS-CoV-2 or SAR-CoV. Importantly, no clinical studies exist supporting that ARBs and ACEIs augment susceptibility to infection and worsen (or improve) all-cause and cardiovascular outcomes in not only COVID-19 patients but also SARS patients at present. Therefore, the hypothesis underlying the concern would not be readily extrapolated to humans, particularly to COVID-19 patients.

In patients with heart failure, prior myocardial infarction, other CVDs, and cerebrovascular disease, the benefit of ARBs and ACEIs has been established in the improvement of quality of life and survival outcomes, while the discontinuation leads to new onset or exacerbation of heart failure, CVD, and stroke and the worsening of the prognosis [42]. Thus, RAS inhibitors should be continued in high-risk patients who have received guideline-directed medical therapy (GDMT). In general, switching from one to another class of antihypertensive agents does not infrequently result in destabilization of blood pressure control and requires frequent visits for drug titration to achieve appropriate and stable blood pressure control and to avoid adverse effects. Blood pressure destabilization increases the incidence of heart failure, stroke, and other CVDs. In addition, frequent visits to the clinic or hospital expose patients to a greater risk of infection in a COVID-19 pandemic situation. Accordingly, even in stably controlled hypertension patients without compelling indications, it is thought that not only simple discontinuation but also switching from ARB or ACEI to other antihypertensive agents should be avoided unless physicians make a decision based on specific considerations.

Cardiovascular comorbidities are common in COVID-19 patients, and such patients are at great risk for morbidity and mortality [1,2,3,4]. Myocardial damage ranging from silent troponin T elevation to fulminant myocarditis has been documented in COVID-19 patients [35]. In confirmed or suspected COVID-19 patients, ACEI and ARB medications are recommended for the treatment of heart failure and other CVD according to GDMT based on the available evidence at this time [35].

In conclusion, at present, the use of ARBs and AECIs should not be withheld in established standard therapy for not only high-risk patients such as those with heart failure, prior myocardial infarction, other CVD, and cerebrovascular disease but also patients with hypertension in stable condition according to the recent statements released by the European Society of Hypertension, the European Society of Cardiology, and the American Heart Association/Heart Failure Society of America/American College of Cardiology [43,44,45]. The evidence on COVID-19 is being accumulated each day. Large-scale clinical studies with convincing evidence, not only RCTs but also real-world big data analyses as well as experimental studies, are awaited to solve the question of whether ARBs and ACEIs have neutral, favorable, or harmful effects on the susceptibility to SARS-CoV-2 and the severity and outcomes of COVID-19.

Finally, we should learn from the lessons of COVID-19 without being bound by common sense in the ante-COVID-19 era. In addition, we should reconstruct a novel strategy for the treatment of hypertension and CVD in the post-COVID-19 era.

Kai, H., Kai, M. Interactions of coronaviruses with ACE2, angiotensin II, and RAS inhibitors—lessons from available evidence and insights into COVID-19. Hypertens Res (2020). doi.org/10.1038/s41440-020-0455-8

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ACE2: Entry Receptor for SARS-CoV-2 May 11, 2020 6:11:16 GMT

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Post by Admin on May 11, 2020 6:11:16 GMT

The role of vitamin D in the prevention of coronavirus disease 2019 infection and mortality
Petre Cristian Ilie, Simina Stefanescu & Lee Smith

Abstract
WHO declared SARS-CoV-2 a global pandemic. The present aim was to propose an hypothesis that there is a potential association between mean levels of vitamin D in various countries with cases and mortality caused by COVID-19. The mean levels of vitamin D for 20 European countries and morbidity and mortality caused by COVID-19 were acquired. Negative correlations between mean levels of vitamin D (average 56 mmol/L, STDEV 10.61) in each country and the number of COVID-19 cases/1 M (mean 295.95, STDEV 298.7, and mortality/1 M (mean 5.96, STDEV 15.13) were observed. Vitamin D levels are severely low in the aging population especially in Spain, Italy and Switzerland. This is also the most vulnerable group of the population in relation to COVID-19. It should be advisable to perform dedicated studies about vitamin D levels in COVID-19 patients with different degrees of disease severity.

Background/aims
WHO declared COVID-19 caused by the virus SARS-CoV-2 a global pandemic. Little is known about the potential protective factors. In the case of COVID-19 we should delineate the protective factors in anti-infective agents that might protect against infection and factors that improve the outcome once the infection has been produced.

Previous observational studies report independent associations between low serum concentration of 25-hydroxyvitanim D and susceptibility to acute respiratory tract infections [1]. In a systematic review and meta-analysis of 25 randomised controlled studies, Martineau et al. has described that vitamin D protected against acute respiratory tract infection overall [2]. In a review of the literature, regarding the possible role of vitamin D in the prevention of influenza virus infection, Gruber-Bzura noticed that the data generate controversies and doubts [3].

Calcitriol (1,25-dihydroxyvitamin D3) exerts pronounced impacts on ACE2/Ang(1–7)/MasR axis with enhanced expression of ACE2 [4]. ACE-2 is the host cell receptor responsible for mediating infection by SARS-CoV-2. Starting from this, it might suggest a higher risk of infection. However, this has not been shown to date and previous studies identified associations between higher levels of ACE2 and better coronavirus disease health outcomes. In the lung, ACE2 was shown to protect against acute lung injury [5].

We hypothesize that vitamin D may play a protective role for COVID-19.

The primary aims of this study are to assess if there is any association between the mean levels of vitamin D in various countries and the mortality caused by COVID-19. The secondary aim was to identify if there is any association between the mean vitamin D levels in various countries and the number of cases of COVID-19.

Results
We have observed a negative correlation between levels of mean vitamin D (average 56.79 nmol/L, STDEV 10.61) and number of cases of COVID-19/1 M population in each country [average 1393.4, STDEV 1129.984, r(20) = − 0.4435; p value = 0.050], and between the mean vitamin D levels and the number of deaths caused by COVID-19/1 M (Fig. 1) [average 80.42, STDEV 94.61, r(20)-value = − 0.4378; p value = 0.05) (Table 1).

Fig. 1

Mean vitamin D levels per courtry versus COVID-19 cases and mortality/1M population

Discussions
We have identified a potential crude association between the mean vitamin D levels in various European countries with COVID-19 cases/1M and COVID-19 mortality.

The European Calcified Tissue Society Working Group has defined severe vitamin D deficiency as a serum 25(OH)D level lower than 30 nmol/L [6].

The Seneca study showed a mean serum vitamin D level of 26 nmol/L in Spain, 28 nmol/L in Italy and 45 nmol/L in the Nordic countries, in older people [6]. In Switzerland, mean vitamin D level is 23 nmol/L in nursing homes and in Italy 76% of women over 70 years of age have been found to have circulating levels below 30 nmol/L [6]. These are the countries with high number of cases of COVID-19 and the aging people is the group with the highest risk for morbidity and mortality with SARS-CoV2. Isaia et al. reported 25(OH)D circulating levels less than 12 ng/mL (30 nmol/L) in 76% of Italian women over 70 years of age, in late Winter [7].

Vitamin D deficiency is a major public health problem worldwide in all age groups [8, 9] but vitamin D status deteriorates with age, above 70 years of life, due to decreased sun exposure and cutaneous synthesis [10]. It is poor in the institutionalized people, 75% of them being severely vitamin D deficient (serum 25(OH)D < 25 nmol/L) [6].

The Southern European countries have lower levels of vitamin D because of decreased exposure (prefer the shade in strong sun) [10] and also as skin pigmentation decreases vitamin D synthesis [11]. Northern part of Europe’s mean levels are better as a consequence of the consumption of cod liver oil and vitamin D supplements as well as fortification of milk and milk products (Finland) [6].

The crude association observed in the present study may be explained by the role of vitamin D in the prevention of COVID-19 infection or more probably by a potential protection of vitamin D from the more negative consequences of the infection.

Regarding the protective role of vitamin D against infection with SARS-Cov2, we can start by looking at the effect on other respiratory infections.

Martineau et al. concluded in a meta-analysis that vitamin D supplementation was safe and protective against acute respiratory tract infections. They described that patients who were severe vitamin D deficient experienced the most benefit [2].

The pathology of COVID-19 involves a complex interaction between the SARS-CoV2 and the body immune system. Calcitriol (1,25-dihydroxyvitamin D3) exerts pronounced impacts on ACE2/Ang(1–7)/MasR axis with enhanced expression of ACE2 [4]. ACE2 is the host cell receptor responsible for mediating infection by SARS-CoV-2. From this perspective it might be apparent that the risk of infection can be higher. However, vitamin D has multiple roles in the immune system that can modulate the body reaction to an infection. Abu-Amer et al. have described that vitamin D deficiency impairs the ability of macrophages to mature, to produce macrophage-specific surface antigens, to produce the lysosomal enzyme acid phosphatase, and to secrete H2O2, a function integral to their antimicrobial function [12]. This might explain, in part, why Martineau et al. have observed that vitamin D was protective in cases of hypovitaminosis [5]. Crucial in the innate immune response are the toll-like receptors which recognise molecules related to pathogens and when activated release cytokines and induce reactive oxygen species and antimicrobial peptides, cathelicins and defensins. Several of the toll-like receptors affect or are affected by vitamin D receptor induction [3].

COVID-19 is caused, beside the virus virulence by the release of pro-inflammatory cytokines. Vitamin D has been found to modulate macrophages' response, preventing them from releasing too many inflammatory cytokines and chemokines [13]. Ciu et al. found that calcitriol (1,25-dihydroxyvitamin D3) exerted pronounced impact on ACE2/Ang(1–7)/MasR axis with enhanced expression of ACE2, MasR and Ang(1–7) generation [4].

Zhen et al. have shown that H5N1 flu infection-induced lung injury can be alleviated by the administration of recombinant human ACE2 protein [14].

Kuka et al. have identified that higher levels of ACE2 are associated with better outcomes for coronavirus disease and it has been shown that in the lung, ACE2 protects against acute lung injury [5].

Xie et al. investigated ACE2 expression in lungs and the effect caused by ageing and gender on its expression, in a rodent model study. The authors described that the decrease of ACE2 was relatively small between the young-adult and the middle-aged groups (25% for male and 18% for female, respectively), but the content of ACE2 decrease by 67% in older female rats and even higher, 78% in older male rats as compared to younger groups [15]. This decrease of ACE2 with age and gender seems to parallel the increase in COVID-19 mortality as well as the higher mortality in the male population.

We acknowledge that this cross-sectional analysis has limitations. The number of cases/country is affected by the number of tests performed and also by the different measures taken by each country to prevent the spread of infection, and the difference in the number of infected patients in the population will also mean different levels of exposure for the population. Mortality might be a better marker of the number of cases in the population although even that can be influenced by the variations in the approach or management of the disease. However, the aim of the present study was to lay out an hypothesis to be taken forward and be investigated utilizing robust study designs.

In conclusion, we found significant crude relationships between vitamin D levels and the number COVID-19 cases and especially the mortality caused by this infection. The most vulnerable group of population for COVID-19, the aging population, is also the one that has the most deficit Vitamin D levels.

Vitamin D has already been shown to protect against acute respiratory infections and it was shown to be safe. It should be advisable to perform dedicated studies about vitamin D levels in COVID-19 patients with different degrees of disease severity.

Ilie, P.C., Stefanescu, S. & Smith, L. The role of vitamin D in the prevention of coronavirus disease 2019 infection and mortality. Aging Clin Exp Res (2020). doi.org/10.1007/s40520-020-01570-8

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ACE2: Entry Receptor for SARS-CoV-2 May 13, 2020 20:28:22 GMT

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Post by Admin on May 13, 2020 20:28:22 GMT

The more we learn about the science behind COVID-19, the more we are beginning to understand the vital role a single molecule in our bodies plays in how we contract the disease.

That molecule, angiotensin-converting enzyme 2, or ACE2, essentially acts as a port of entry that allows the coronavirus to invade our cells and replicate. It occurs in our lungs, but also in our heart, intestines, blood vessels and muscles.

And it may be behind the vastly different death rates we are seeing between men and women.

What is ACE2?
ACE2 is an enzyme molecule that connects the inside of our cells to the outside via the cell membrane.

In normal physiology, another enzyme called ACE alters a chemical, angiotensin I, and converts it into angiotensin II, which causes blood vessels to constrict. The tightening of the blood vessels leads to an increase in blood pressure.

That’s when the ACE2 molecule comes in: to counteract the effects of ACE, causing blood vessels to dilate and lowering blood pressure.

You may have seen illustrations of the virus that show distinct spikes around the surface of the virus, which form part of the “crown” or “corona” that gives the virus its name. These spikes are called S1 proteins, and they are what bind to the ACE2 molecule on our cells.

The virus is then able to invade the cell by a process called endocytosis – where the cell membrane engulfs the virus and internalises it within a bubble called an endosome.

Once inside the cell, the virus interacts with the host cells’ genetic machinery, taking advantage of the existing structure to replicate extensively.

SARS-CoV-2, the virus behind COVID-19, has a high binding capacity for ACE2 – between ten and 20 times more that of the original Sars virus. This means it is much easier for SARS-CoV-2 to get into human cells compared to the original coronavirus, making it more infectious overall.

ACE2 and COVID-19
But there is still conflicting evidence on the precise role ACE2 plays in coronavirus infections.

In some cases, it can actually be of benefit: ACE2 has been shown to reduce injury to the lung tissue in cases of the original Sars virus in mice by doing its job and causing blood vessels to dilate.

In another mouse study, however, the binding of the Sars spike protein to ACE2 was shown to contribute to lung damage.

When it comes to the current coronavirus, early studies have shown that the introduction of a human-made form of ACE2 to human cells can block the early stages of infection by binding the spike protein, preventing it from entering the cells. ACE2 thus acts both as an entry port to cells but also as a mechanism to protect the lung from injury.

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ACE2: Entry Receptor for SARS-CoV-2 May 21, 2020 19:05:14 GMT

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Post by Admin on May 21, 2020 19:05:14 GMT

Previous data from COVID-19 patients suggests that cigarette smokers are more likely to have health complications. One possible reason, researchers report May 15 in the journal Developmental Cell, is that smoking increases the gene expression of ACE2—the protein that binds SARS-CoV-2—which may promote COVID-19 infection. The study suggests that prolonged smoking could cause an increase of the ACE2 protein in the lungs, possibly resulting in a higher rate of morbidity in patients.

"Our results provide a clue as to why smokers who develop COVID-19 tend to have poor clinical outcomes," says senior author Jason Sheltzer, a cancer geneticist at Cold Spring Harbor Laboratory. "We found that smoking caused a significant increase in the expression of ACE2, the protein that SARS-CoV-2 uses to enter human cells."

ACE2, or Angiotensin Converting Enzyme 2, is a regulatory protein that has been linked to vulnerability to the 2003 SARS (2003) virus. "Evidence from mouse experiments has shown that higher levels of ACE2 make mice more susceptible to SARS," says Sheltzer. More recent work with SARS-CoV-2 found that when human ACE2 was highly expressed in mice infected with COVID-19, they died more quickly."

In humans, the lungs act as one of the primary locations of ACE2 production. To assess the direct impact of smoking on ACE2 expression in the lungs, Sheltzer compared ACE2 gene expression from the lung epithelial tissue of people who smoked cigarettes regularly to those who had never smoked. "We found that smoking caused a significant increase in the expression of ACE2," says Sheltzer, who noted that smokers produced 30%-55% more ACE2 than their non-smoking counterparts. This change was also dose dependent, with heavy smokers having the greatest ACE2 values.

The effects of smoking on ACE2 may be tied to the goblet cells in the lungs—one of the few lung cell types that Sheltzer found to actively express the ACE2 gene. "Goblet cells produce mucous to protect the respiratory tract from inhaled irritants. Thus, the increased expression of ACE2 in smokers' lungs could be a byproduct of smoking-induced secretory cell hyperplasia" says Sheltzer. An uptick in ACE2 was also associated with the inflammatory pulmonary diseases COPD and idiopathic pulmonary fibrosis.

Additionally, Sheltzer's results indicate that other viral infections, such as influenza, as well as interferon signaling—the part of the body's virus defense system—increase ACE2 expression. "Because of this, it's conceivable that SARS-CoV-2 could trigger the upregulation of its own receptor, thereby creating a positive feedback loop leading to more infections," Sheltzer says.

While the impact of cigarette smoke and ACE2 expression is compelling, it is not permanent. By comparing the lungs of current smokers to those who quit smoking for at least 12 months, Sheltzer found "a significant decrease in ACE2 expression, demonstrating that the effects of smoking on ACE2 can be reversed." Further, other studies on the effects of cigarette smoke have shown mixed results. "Cigarette smoke contains hundreds of different chemicals. It's possible that certain ingredients (like nicotine) have a different effect than whole smoke does," says Sheltzer.

And while Sheltzer finds strong support for the upregulation of ACE2 gene expression from smoking, the actual ACE2 protein may be regulated in ways not addressed in this study. "One could imagine that having more cells that express ACE2 could make it easier for SARS-CoV-2 to spread in someone's lungs, but there is still a lot more we need to explore."

Abstract
The factors mediating fatal SARS-CoV-2 infections are poorly understood. Here, we show that cigarette smoke causes a dose-dependent upregulation of Angiotensin Converting Enzyme 2 (ACE2), the SARS-CoV-2 receptor, in rodent and human lungs. Using single-cell sequencing data, we demonstrate that ACE2 is expressed in a subset of secretory cells in the respiratory tract. Chronic smoke exposure triggers the expansion of this cell population and a concomitant increase in ACE2 expression. In contrast, quitting smoking decreases the abundance of these secretory cells and reduces ACE2 levels. Finally, we demonstrate that ACE2 expression is responsive to inflammatory signaling and can be upregulated by viral infections or interferon treatment. Taken together, these results may partially explain why smokers are particularly susceptible to severe SARS-CoV-2 infections. Furthermore, our work identifies ACE2 as an interferon-stimulated gene in lung cells, suggesting that SARS-CoV-2 infections could create positive-feedback loops that increase ACE2 levels and facilitate viral dissemination.

Graphical Abstract

More information: Joan C. Smith et al, Cigarette smoke exposure and inflammatory signaling increase the expression of the SARS-CoV-2 receptor ACE2 in the respiratory tract, Developmental Cell (2020). DOI: 10.1016/j.devcel.2020.05.012