Data were generated by the O’Beirne research group.  The relationship between ACE2 expression in the small airway epithelium (SAE) and average monthly pollution levels in New York City, using data from the EPA, was assessed.  There was no difference reported between expression and pollution levels in nonsmokers (white dots), smokers (gray dots), or a combination of the two groups.  It should be noted that the maximum 30-day mean PM2.5 concentration was 18 μg/m^3 which is considered safe by the EPA.  

ACE2 Expression in the Small Airway Epithelium is Not Associated with Air Pollution in New York City

- Smoking Upregulates Angiotensin-Converting Enzyme-2 Receptor: A Potential Adhesion Site for Novel Coronavirus SARS-CoV-2 (Covid-19)

Clinical imaging data suggest that the small airway epithelium (SAE) in an important SARS-CoV-2 binding site.  
- expression versus nonsmokers
- expression versus nonsmokers by sex

ACE2 Expression in the Airway Epithelium of Smokers

- expression in the tracheobronchial tree
- expression in primary basal cells
- expression by cell type in the small airway

ACE2 Expression in the Airway Epithelium of Healthy Nonsmokers

A main feature of symptomatic COVID-19 disease is respiratory infection. Severe damage to the lungs during respiratory distress may cause pulmonary fibrosis, necessitating lung transplants. Lasting damages to the lungs may occur even in recovering patients with mild infections. SARS-CoV-2 targets the following cell types:

- Type I pneumocytes (AT1) 
- Type II pneumocytes (AT2) 
- alveolar macrophages

ACE2 expression is primarily seen in AT2 cells which have been shown to be involved in the reproduction and transmission of the virus.  Viral targeting of alveolar macrophages is evidenced by N antigen expression.

Effects of COVID-19 on the Lungs

miRNAs that are homologous to the 3' end of the ACE2 gene were assessed using the data set from the Wang research group to determine if ACE2 expression was modulated by smoking.  miR-1246 is complementary to the  3′ untranslated region (3′UTR) of ACE2 mRNA.  Predicted base pairing was assessed using TargetScanHuman 7.2 (http://www.targetscan.org/vert_72/).  Affymetirx miRNA 2.0 arrays and TaqMan PCR reveal that miR-1246 expression is significantly decreased in smokers compared to nonsmokers (**P < 0.01 and ***P < 0.001).  This miRNA may be involved in the mechanism that regulates ACE2 expression in the SAE. 

miR-1246 Levels May Modulate ACE2 Expression Levels in the Small Airway Epithelium

BCi-NS1.1 cells were derived from a single basal cell from the large airway epithelium (LAE) of a healthy nonsmoker, and hSABCi-NS1.1 cells were derived from a single basal cell from the small airway epithelium (SAE) of a healthy nonsmoker.  Expression levels were determined using HiSeq 4000 RNA-seq data at day 0 (baseline) and after 28 days on an air-liquid interface (ALI).  Notable findings include:

- Both cell lines showed an increase in ACE2 expression after 28 days of differentiation
- ADAM10, ADAM17, FURIN, CTSL, and PI4KB expression was relatively maintained throughout differentiation in both cell lines
- TMPRSS2 was notably less expressed in undifferentiated LAE basal cells than in SAE basal cells, and their expression increased.  However, its expression was maintained in SAE basal cells.  
- TPRSS11A and TMPRSS11D expression remained low in both LAE and SAE cells throughout differentiation

Because these cell lines are immortal, they may continue to be useful in SARS-CoV-2 research - especially for early drug screening.  

ACE2 and Other Cellular Proteins Related to B-Coronavirus Infection Expression Increases in Basal Cells from the Large Airway Epithelium Throughout Differentiation

One of the primary manifestations of COVID-19 is respiratory disease.  ACE2 expression was assessed in human airway epithelial tissue to better understand how SARS-CoV-2 interacts. with these cells. Studies included:

- ACE2 expression in healthy nonsmokers
- ACE2 expression in smokers
- ACE2 expression modulation by air pollution
- ACE2 expression modulated by miRNA (miR-1246)
- ACE2 expression in basal cells from the large and small airway epithelia of healthy nonsmokers

Michigan State University

Smoking as a Risk Factor for COVID-19

- cancer tissue
- human airway epithelium tissue
- human brain expression
- protein and mRNA expression
- relationship to COVID-19

ACE2 Expression in Tissue and Organs

Zhang, H., Rostami, M. R., Leopold, P. L., Mezey, J. G., O'Beirne, S. L., Strulovici-Barel, Y., & Crystal, R. G. (2020). Expression of the SARS-CoV-2 ACE2 Receptor in the Human Airway Epithelium. American Journal of Respiratory and Critical Care Medicine, (ja).
https://www.atsjournals.org/doi/full/10.1164/rccm.202003-0541OC
doi: 10.1164/rccm.202003-0541OC   

Expression of the SARS-CoV-2 ACE2 Receptor in the Human Airway Epithelium

ACE2 Expression in Human Airway Epithelial Tissue

The authors identified 19 peer-reviewed papers (16 from China, 1 from Korea, and 2 from U.S.) published before April 28, 2020 on COVID-19 patients with data on smoking behavior. The analysis consisted of 11,590 COVID-19 patients, 731 (6.3%) with a history of smoking. Among the patients with a history of smoking, 29.8% experienced COVID-19 progression, compared to 17.6% non-smoking patients who experienced disease progression (OR 1.91, 95% CI 1.42-2.59). 
*"There was moderate heterogeneity among the studies (I2=38%, p=.048) and no significant evidence of publication bias (Harbord’s p=.813, Peters’ p=.941)."

Smoking Is Associated With COVID-19 Progression: A Meta-analysis

Researchers from Stanford University conducted a cross-sectional survey online of U.S. adolescents (13-24 years old) to assess if e-cigarette and cigarette usage increases the risk of being infected with COVID-19.  There were 4,351 respondents to the survey.  It was found that past 30 day dual users (use both e-cigarettes and cigarettes only within the last 30 days) were 6.8 times more likely to test positive for COVID-19.  Ever users of e-cigarettes (use only e-cigarettes) were five times more likely to test positive for COVID-19, while ever dual users (use both e-cigarettes and cigarettes) were seven times more likely to test positive for COVID-19.  


E-cigarette users and dual users are most likely at higher risk for being infected with COVID-19 because being exposed to nicotine and other chemicals within e-cigarettes has a negative effect on respiratory health, specifically on proper lung functioning.  Additionally, the act of sharing e-cigarette devices is common among adolescent e-cigarette users, serving as a potential pathway of infection from one individual to another.  Considering that e-cigarette usage is very widespread in the U.S., especially among adolescents, it can be concluded that adolescent e-cigarette usage is further exacerbating the COVID-19 pandemic.  

E-Cigarette and Cigarette Use is Associated with a Higher Risk of COVID-19

According to the GEPIA dataset, nearly all cancer tissues can express ACE2 with renal cancer having the highest expression level.  Some cancerous tissues were found to have a significant increase in ACE2 when compared against the same noncancerous tissue.  

Cancer Tissue Expression of ACE2

Expression levels were determined using the HPA (https://www.proteinatlas.org).  Tissues that express ACE2 were broken down into five categories based off of the amount of ACE2 mRNA expression:

- (1, highest expression, score range: 122-10) small intestine, colon, duodenum, kidney, testis, gallbladder and heart muscle
- (2, medium high expression, score range: 5-1) adipose tissue, thyroid gland, epididymis, ductus deferens, breast, pancreas, rectum, ovary, esophagus, liver, seminal vesicle, salivary gland and placenta
- (3, medium low expression, score range: 0.9-0.5) vagina, lung, appendix, skeletal muscle, fallopian tube, lymph node, tongue, stomach and prostate
- (4, low expression, score range: 0.4-0.1) remaining tissues
- (5, no expression, score range: 0) parathyroid gland, bone marrow, monocytes, B-cells, NK-cells, dendritic cells and total peripheral blood mononuclear cell

ACE2 Protein and mRNA Expression in Tissue

ACE2 is known to be expressed in a variety of different tissues, including:

- Heart, kidneys, gastrointestinal (GI) tract, lungs, brain, testes, bladder, adipose tissue, vascular system, cholangiocytes (epithelial cells of the oral and nasal mucosa)

ACE2 expression may explain the SARS-CoV-2 organ localization.

Expression of ACE2 in Tissue and COVID-19

ACE2 expression was quantified in 21 regions of the human brain using multiple tissue expression (MTE) arrays (*p < 0.01 (ANOVA); error bars represent one standard deviation of the mean).  The highest expression was found in the pons, amygdala, and the medulla oblongata.  The pons and medulla oblongata are notably known to control breathing and respiration. 

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