ACE2 and furin levels linked to inflammation in smokers with COVID-19

Many risk factors for adverse outcomes in coronavirus disease 2019 (COVID-19) have been identified, including obesity, heart disease and diabetes mellitus. Smoking is involved in aggravating or contributing to the disease process in several conditions, including infections.

A new preprint on the medRxiv* server reports the level of angiotensin-converting enzyme 2 (ACE2) and furin, two enzymes that are intimately linked to infection with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), the causative agent of COVID-19.

The ACE2 receptor

COVID-19 is a primarily pneumonic condition, with most terminally ill patients displaying signs of acute respiratory failure. Often, however, this is linked to multi-organ dysfunction with underlying vascular damage and thrombosis. The virus is thought to enter through the host membrane receptor, ACE2, which is found at high levels in lung epithelium. Among the various types of respiratory cells, the type II pneumocytes, goblet cells, epithelial and ciliated cells of the nose, and the cells of the oral mucosa, are found to have the highest expression of this receptor.

ACE2 also has physiological activity, since it converts the vasoactive hormone angiotensin 2 to vasodilatory metabolites, thus preventing the harmful effects of the former molecule. Despite the intense focus on this receptor with the pandemic's onset, it is still unclear as to the change induced in ACE2 by the virus. There are two possibilities: either its activity is modulated, or its expression is modified.

Smoking and COVID-19 risk

Several early reports have suggested that smokers face a lower risk from COVID-19, but this conclusion is now suspect, because of more recent data. For instance, a meta-analysis of 15 studies, including over 2,400 people, showed that COVID-19 was likely to be more severe and deadly in patients who currently smoke. Another study showed that the rate of progression of COVID-19 is almost double in smokers compared to that in non-smokers.

The researchers aimed to identify a possible association between smoking and systemic inflammatory markers, and between the sex of the individual and the expression of ACE2 and furin. ACE2 levels have been suggested to be higher in the lungs of smokers, but this has not been studied with respect to the risk of development and severity of COVID-19.

The researchers obtained serum samples from patients with COVID-19 and those who had recovered from the infection, with and without a history of smoking.

Smokers with COVID-19 have higher levels of inflammatory cytokines

Acute COVID-19 is known to be characterized by high levels of inflammatory mediators. The current study therefore looked at 27 cytokines and chemokines.

They found that inflammatory cytokines such as IL-1α, IL-8, IL-2, VEGF and IL-10, were expressed at higher levels in patients with COVID-19 relative to controls without the infection. Among COVID-19 patients with a history of smoking, there was a marked increase in the production of certain specific cytokines, such as IFN-γ, 43 Eotaxin, MCP-1 and IL-9, compared to those who did not smoke. Interestingly, the latter subset of cytokines is associated with hyperactive inflammation, suggesting that smoking worsens the severity of COVID-19.

Smoking increases ACE2 levels in COVID-19 patients

SARS-CoV-2 entry into host cells is mediated by ACE2, which was increased in the serum of COVID-19 patients compared to the controls. However, the researchers also found higher levels in the serum of COVID-19 patients with a past or current history of smoking, relative to controls (non-smokers). Males had higher ACE2 levels than females.

“Our results show that age and smoking status play a crucial role in governing the COVID-19 related enzyme activity in human subjects.”

Smoking increases furin levels in COVID-19 patients who smoke

Furin levels in serum were also higher in COVID-19 patients with a history of smoking, as above, compared to non-smokers with COVID-19. Males showed a trend towards increased furin levels. Furin is a proprotein convertase that is crucial to the mechanism of SARS-CoV-2 infection.

COVID-19 associated with changes in lipid profile

Lipid mediators such as prostaglandins are often altered during infections, and may decrease or exaggerate the associated inflammation. The researchers showed the presence of a discriminatory lipid profile among COVID-19 patients vs. those who had recovered from the infection. The affected lipid markers include PGF2α, HETEs, LXA4 and LTB4 – from prostaglandin, hydroxyeicosatetraenoic acid, lipoxin and leukotriene pathways, respectively. However, smoking did not appear to be linked to changes in these lipid pathways.

What are the implications?

Overall, the study shows that inflammatory molecules are markedly higher in smokers with COVID-19 relative to controls. The researchers also demonstrated increased levels of cytokines and furin in patients with active COVID-19 relative to recovered patients.

These findings suggest the feasibility of developing these molecules as biomarkers to stratify COVID-19 patients by disease severity, to optimize their management. As hospitals and healthcare systems worldwide are increasingly stretched, these sorts of biomarkers can help them prioritize care and resources through more accurate disease outcome predictions.

The study suggests that COVID-19 is associated with a distinctive profile of systemic inflammatory markers and molecules that facilitate or mediate viral-host interactions. These are adversely impacted by smoking, indicating a higher risk of poor outcomes among COVID-19 patients who have a history of smoking.

Further research could tease out the effects of vaping and the perceived persistence of high ACE2 levels in recovered patients, which may underlie the ‘long-haul’ symptoms being reported in many COVID-19 convalescents.

*Important Notice

medRxiv 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.

Journal reference:
Dr. Liji Thomas

Written by

Dr. Liji Thomas

Dr. Liji Thomas is an OB-GYN, who graduated from the Government Medical College, University of Calicut, Kerala, in 2001. Liji practiced as a full-time consultant in obstetrics/gynecology in a private hospital for a few years following her graduation. She has counseled hundreds of patients facing issues from pregnancy-related problems and infertility, and has been in charge of over 2,000 deliveries, striving always to achieve a normal delivery rather than operative.


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