Despite having numerous negative health consequences, the epidemiological relationship between cigarette smoking and severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection is controversial.
Now, a new study published on the bioRxiv* preprint server investigates this relationship further and suggests that current smoking is not associated with a higher incidence of SARS-CoV-2 infection.
Comorbidities, such as diabetes, hypertension, and obesity, are associated with severe COVID-19. Separately, there is ample evidence of smoking leading to adverse health conditions like cancer, cardiovascular diseases, and chronic respiratory illness.
During the ongoing pandemic, there has been a keen interest in trying to understand the link between cigarette smoking and the contraction of coronavirus disease 19 (COVID-19). Smoking can cause chronic obstructive pulmonary disease (COPD), which is associated with severe clinical outcomes in COVID-19 patients.
Previous studies have linked COPD to increased expression of angiotensin-converting enzyme 2 (ACE2) – the main receptor of SARS-CoV-2. A high presence of ACE2 in conducting pathways could increase susceptibility to SARS-CoV-2 infection. However, some studies showed that the presence of ACE2 in the pulmonary vasculature could be beneficial during the advanced stages of the disease.
A New Study
In the current study, scientists explored the above-mentioned link between ACE2 and COVID-19 disease. They conducted an in vitro study using differentiated primary human bronchial airway epithelial cells (HBECs) at the air-liquid interface (ALI). These and similar nasal cells are present at the entry point of SARS-CoV-2. It was, therefore, rational to expose these in vitro human airways to SARS-CoV-2 in the presence and absence of cigarette smoke. This helped scientists understand the role played by smoking in the early stage of infection.
Quantitative PCR, immunofluorescence, and western blotting approaches were used to demonstrate that cigarette smoke-induced ACE2 expression in HBECs. This robust methodology delivered results consistent with molecular epidemiological data linking ACE2 expression and smoking. Interestingly, in the experiments conducted, increased expression of ACE2 (as a result of the cigarette smoke extract (CSE)) did not substantially alter the quantity of cells infected, in percentage terms. Once again, this is consistent with prior knowledge that smoking is not a major risk factor with respect to infection.
Scientists have deliberated on the potential reasons why CSE had a muted impact on HBECs, despite the elevation of ACE2. One explanation is that the CSE upregulated the truncated isoform (dACE2), which lacks the SARS-CoV-2 binding domain. Researchers showed that CSE mainly induced the expression of the full-length isoform. However, the cells retained the potential to upregulate dACE2 in response to IFNα. It must be noted that the above results differed from recently published data that failed to detect increased ACE2 in response to cigarette smoke. However, this discrepancy could be due to the differences in the smoking protocols used.
Modulating ACE2 Expression and COVID-19
Scientists have been investigating the possibility of modulating ACE2 expression to influence the course of the pandemic. In this regard, it might be useful to distinguish between conducting and distal airways, which have different characteristics. A reduction in ACE2 in the conducting airway (where SARS-CoV-2 infects first) may hamper the protective impact of ACE2 in the distal airway. In the current study, scientists showed that elevated full-length isoform (flACE2) has no impact on cellular infection.
Researchers also showed that oltipraz, an NFR2 agonist already in Phase 3 clinical trials, increased ACE2 in HBECs, contrary to expectations. Nicotine, a component of cigarette smoke, is also being actively investigated with respect to its ability to protect against COVID-19. The data obtained in the current study showed that nicotine did not substantially alter ACE2 or CHRNA7 mRNA expression in HBECs, 48 hours after treatment.
The study has a few limitations. One limitation is that it focussed on the conducting airways only. Therefore, the results are valid for the earlier stages of infection rather than the later stages when most people require critical care and hospitalization. Further, ALI epithelial cultures are not able to model the systemic impacts of smoking. The ALI differentiated models have significant advantages, but they likely did not detect subtle changes in the susceptibility to infection.
It is known that individuals with chronic respiratory and/or cardiovascular disease are more vulnerable to severe COVID-19 infection. However, smokers are just as susceptible to SARS-CoV-2 as the general public. This study showed that cigarette smoke brought about an increase in full-length ACE2 but not an increased vulnerability to infection. Researchers also showed that an increase in ACE2 receptor expression, brought about by therapeutics, is unlikely to bring about an increase in cellular infection.
bioRxiv publishes preliminary scientific reports that are not peer-reviewed and, therefore, should not be regarded as conclusive, guide clinical practice/health-related behavior, or treated as established information.
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