Studying the effects of tobacco smoking on the risk of COVID-19

A study conducted by researchers in China has shed light on how certain tobacco compounds can prevent cells from becoming infected with coronavirus 2 (SARS-CoV-2), the causative agent of coronavirus disease 2019 (COVID-19).

Given that tobacco smoking is associated with more severe COVID-19 in those infected, and that the compounds identified are carcinogenic, the general advice on smoking cessation remains valid, the study authors say.

“Tobacco use should not be recommended and a smoking cessation plan should be established for smokers in COVID-19 pandemic,” write Guang-Biao Zhou (Chinese Academy of Medical Sciences, Beijing) and colleagues.

A pre-print version of the paper is available on the server medRxiv * while the article is being peer reviewed.

Schematic representation of the ACE2 degradation induced by tobacco smoke.

The smoking controversy and COVID-19

“The relationship between tobacco smoking and the incidence and severity of COVID-19 remains controversial,” the researchers said.

Since the COVID-19 pandemic began in Wuhan, China late last year, an unexpected finding has been that smokers account for only about 1.4% to 18.5% of hospital admissions.

However, according to the World Health Organization, smoking has been linked to increased rates of severe COVID-19 and death.

Tobacco smoke causes more than 8 million deaths worldwide each year, with 7 million dying from the effects of smoking and 1.2 million from the effects of second-hand smoking.

“A great effort should be made to reduce tobacco use and help smokers quit,” said Zhou and the team.

What have studies found so far?

As researchers noticed links between tobacco smoking and COVID-19 incidence, significant efforts have been made to determine the role of tobacco smoking in SARS-CoV-2 infection.

So far, studies have shown that the levels of angiotensin converting enzyme 2 (ACE2) – the host cell receptor for SARS-CoV-2 – are higher in the lung tissue of non-smokers than that of smokers. Studies have also shown that tobacco carcinogens downregulate ACE2 in mice.

In addition, Zhou and colleagues say a study showed that cigarette smoke extract (CSE) inhibited SARS-CoV-2 spike protein pseudovirus infection, supporting findings that smokers were at lower risk for one compared to smokers SARS-CoV-2 infections have average population.

The spike protein is the main surface structure that the virus uses to bind to ACE2 and gain access to host cells. Pseudoviruses are virus-like particles that cannot replicate and are therefore useful tools in virology research because of their safety and versatility.

Among the tobacco compounds tested, it was benzo (a) pyrene-BaP and nicotine-derived nitrosamine ketone (NNK) that prevented the pseudovirion of the SARS-CoV-2 spike protein from infecting cells. Both substances are notorious carcinogens that have various adverse health effects, the team says.

Another study also showed that BaP triggers upregulation of the oncoprotein Skp2, which plays an essential role in the progression and proliferation of the cell cycle.

What did the current study find out?

The researchers showed that CSE and BaP in samples taken from normal lung tissues exert a double effect on ACE2, on the one hand upregulating the ACE2 mRNA and on the other hand triggering the catabolism of the ACE2 protein.

BaP induced a significant upregulation of Skp2, which interacts with ACE2 and induces ubiquitination and subsequent degradation of the substrate.

“Proteasome and lysosome are two critical points for the breakdown of ubiquitinated substrate proteins,” write Zhou and colleagues.

The team found that the lysosome was partially responsible for the BaP-induced breakdown of ACE2. When human bronchial epithelial cells (16HBE) were co-incubated with 40 µM of the lysosome inhibitor chloroquine for 36 hours, ACE2 was partially rescued from BAP-induced catabolism.

The proteasome also played a role in the catabolism of ACE2; When the cells were co-incubated with 10 µM of the proteasome inhibitor MG132 for 12 hours, the degradation of ACE2 was again partially suppressed.

“The fact that inhibition of the proteasome or the lysosome can partially but not completely block the breakdown of ACE2 suggests that both organelles are critical to ACE2 catabolism and the role of other forms of post-translational modification in ACE2 catabolism Requires investigations, “he writes The Team.

“Tobacco Consumption Should Not Be Recommended”

The researchers say their results partially reveal the mechanisms underlying the effects of tobacco carcinogens on ACE2. Whether ACE2 proteolysis can explain the severity of the disease in COVID-19 patients needs to be determined in future studies.

In the meantime, the team points out that ACE2 is required to maintain lung and cardiovascular functions.

Given that tobacco smoke causes 8 million deaths, including 2.1 million cancer deaths per year, and Skp2 is an oncoprotein, tobacco use should not be recommended and a smoking cessation plan should be established for smokers in COVID-19 pandemic, “conclude Zhou and colleagues .

* Important NOTE

bioRxiv publishes preliminary scientific reports that are not peer-reviewed and should therefore not be considered conclusive, guide clinical practice / health-related behavior, or are treated as established information.