A study conducted by researchers in China has shed light on how certain tobacco compounds might prevent cells from becoming infected with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), the agent that causes coronavirus disease 2019 (COVID-19).
However, given that tobacco smoking is associated with more severe COVID-19 among those who become infected and that the compounds identified were carcinogens, the generalized advice to quit smoking remains valid, say the study authors.
“Tobacco use should not be recommended, and a cessation plan should be prepared 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 in the server medRxiv* while the article undergoes peer review.
Schematic representation of tobacco smoke-induced ACE2 degradation.
The controversy surrounding smoking and COVID-19
“The association between tobacco smoking and COVID-19 incidence and severity remains controversial,” said the researchers.
Since the COVID-19 pandemic began in Wuhan, China, late last year, one unexpected finding has been that smokers only make up around 1.4 to 18.5% of hospitalizations.
However, according to the World Health Organization, smoking is associated with increased rates of severe COVID-19 and death.
Tobacco smoke also accounts for more than 8 million deaths per year globally, with 7 million dying from smoking and 1.2 million dying due to exposure to second-hand smoke.
“Great efforts should be made to reduce tobacco use and help smokers to quit,” say Zhou and team.
What have studies found so far?
Since researchers noticed associations between tobacco smoking and COVID-19 incidence, significant efforts have been made to determine the role tobacco smoking might play in SARS-CoV-2 infection.
So far, studies have shown that 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 in that of smokers. Studies have also shown that tobacco carcinogens downregulate ACE2 in mice.
Furthermore, Zhou and colleagues say one study showed that cigarette smoke extract (CSE) inhibits SARS-CoV-2 spike protein pseudovirus infection, thereby supporting findings that smokers may be at a lower risk of SARS-CoV-2 infection, as compared with the general population.
The spike protein is the main surface structure the virus uses to bind to ACE2 and gain access to host cells. Pseudoviruses are virus-like particles that lack the ability to replicate and are, therefore, useful tools in virology research, owing to their safety and versatility.
Among the tobacco compounds tested, it was benzo(a)pyrene BaP and nicotine-derived nitrosamine ketone (NNK) that stopped the SARS-CoV-2 spike protein pseudovirion from infecting cells. Both of these substances are notorious carcinogens that have various adverse health effects, says the team.
Another study has also shown that BaP triggers upregulation of the oncoprotein Skp2, which plays an essential role in cell cycle progression and proliferation.
What did the current study find?
The researchers showed that in specimens harvested from normal lung tissues, CSE and BaP exert a dual effect on ACE2, upregulating ACE2 mRNA on the one hand and triggering catabolism of the ACE2 protein on the other.
BaP induced significant upregulation of Skp2, which interacts with ACE2 and induces ubiquitination and subsequent degradation of the substrate.
“Proteasome and lysosome are two critical sites for degradation of ubiquitinated substrate proteins,” writes Zhou and colleagues.
The team found that the lysosome was partially responsible for the BaP-induced degradation of ACE2. When human bronchial epithelial (16HBE) cells were co-incubated with 40 µM of the lysosome inhibitor chloroquine for 36 hours, ACE2 was partially rescued from BAP-triggered catabolism.
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 either proteasome or lysosome can partially but not completely block the degradation of ACE2 suggests that both organelles are critical to ACE2 catabolism, and the role of other forms of post-translational modification in ACE2 catabolism warrants further investigation,” writes the team.
“Tobacco use should not be recommended”
The researchers say their results partially unveil the mechanisms underlying the action of tobacco carcinogens on ACE2. Whether ACE2 proteolysis can account for disease severity among COVID-19 patients needs to be determined in future studies, they add.
In the meantime, the team points out that ACE2 is required to maintain lung and cardiovascular functions.
Furthermore, “given that tobacco smoke accounts for 8 million deaths including 2.1 million cancer deaths annually and Skp2 is an oncoprotein, tobacco use should not be recommended and cessation plan should be prepared for smokers in COVID-19 pandemic,” conclude Zhou and colleagues.
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.