Smokers may be prone to severe COVID-19 infections, in part, because their lungs contain an abundance of entry points that the virus can exploit.

COVID-19 infections begin at the ACE2 receptor , a protein nestled on the surface of cells throughout the body, including in the upper and lower respiratory tracts. The coronavirus that causes COVID-19, known as SARS-CoV-2, must plug into the ACE2 receptor in order to inject its genetic material into cells, replicate and spread. Now, preliminary research suggests that lungs exposed to cigarette smoke accumulate abnormally large numbers of ACE2 receptors, which may leave the organ vulnerable to damage inflicted by the coronavirus.

"It has been reported that smokers who get COVID-19 tend to have more severe infections than individuals who aren’t smokers," co-author Jason Sheltzer, a research fellow at the Cold Spring Harbor Laboratory in New York, told Live Science in an email. An increase in ACE2 receptors "could be one reason — of many — why smokers get so sick from coronavirus," he said.

The study, posted March 31 to the preprint database bioRxiv , has not been peer-reviewed and its premise remains "fairly speculative," said Dr. Stephanie Christenson, an assistant professor in the Division of Pulmonary, Critical Care, Allergy, and Sleep Medicine at University of California, San Francisco, who was not involved in the study.

"If ACE2 expression is high, if ACE2 expression is low, and what that means toward your overall prognosis — I don't think we actually know that yet," Christenson told Live Science.

"Smoking does a lot of things to the body," Sheltzer added. "And it’s possible that [smoking's] effect on ACE2 levels isn’t the most important factor."

Smoking linked to severe infection

Mounting evidence suggests that, compared with nonsmokers, people who smoke cigarettes face a higher risk of developing severe complications and dying from COVID-19 infections.

For instance, a study of more than 1,000 patients in China, published in the New England Journal of Medicine , found that smokers with COVID-19 were more likely to require intensive medical interventions than those who didn't smoke. In the study, 12.3% of current smokers were admitted to an ICU, were placed on a ventilator or died, as compared with only 4.7% of nonsmokers.

Smokers may be particularly vulnerable to COVID-19 for several reasons, but the ACE2 receptor hypothesis "provides a holistic, mechanistic link" between smoking and severe infection, Jaber Alqahtani, a researcher in Respiratory Medicine at University College London, told Live Science in an email. If future research bolsters the link between receptor quantity and disease severity, drugs that block or reduce the sensitivity of ACE2 receptors could potentially be used as treatments, he added.

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More gateways into the lung

To draw the connection between ACE2 receptors and smoking, Sheltzer and software engineer Joan Smith, a member of Sheltzer's lab, examined lung and respiratory tissue samples from deceased mice, rats and humans, as well as samples collected during human lung surgeries. The number of ACE2 receptors in the lungs did not vary between rodents of different ages or different sexes, and the same trends appeared in humans.

As age and sex appeared unrelated to ACE2 quantity, the researchers wondered if cigarette smoke exposure might make a difference.

The team inspected tissue samples from mice that had been exposed to diluted cigarette smoke for zero, 2, 3 or 4 hours a day over the course of five months. They found that, the more smoke exposure, the more ACE2 receptors studded the animals' lungs. Compared with unexposed mice, the mice that received the highest dose of cigarette smoke accumulated about 80% more ACE2 receptors in their lungs. The researchers then compared the lungs of human smokers against those who never smoked, and again, they found a similar trend: Smokers’ lungs contained 40% to 50% more ACE2 receptors than those of nonsmokers.

The quantity of ACE2 receptors varied by pack-years — a measure of how many packs of cigarettes a person smoked per day multiplied by the number of years the person smoked. For example, among smokers who had undergone thoracic surgery, people who smoked more than 80 pack-years showed a 100% increase in ACE2 receptors compared with people who smoked fewer than 20 pack-years, the authors noted.

While smoke-exposed tissues harbored more ACE2 receptors, the team could not tell which specific cells contained the receptor. By examining which proteins appeared in what cells, the team found that ACE2 appeared on cells that process oxygen and carbon dioxide in the lungs, known as alveolar type 2 cells. But primarily, the receptors appeared on cells that secrete a mucus-like fluid into the respiratory tracts, known as goblet and club cells. Nonsmokers carry most of their goblet and club cells in their nose and throat, but in smokers, the cells begin to accumulate also in the lungs, the authors found.

"What they're suggesting is that when you smoke you have an increase in goblet cells [in the lower respiratory tract], and that's definitely true," Christenson said.

Evidence that smoking boosts the number of secretory cells in the lungs has been reported for decades, according to a 1999 report in the American Journal of Respiratory and Critical Care Medicine . The sticky mucus generated by goblet and club cells acts as a protective barrier, capturing debris, aerosols, smoke and pathogens that get sucked into the respiratory system, Christenson said. When people inhale smoke into their lungs, the organ reinforces its defenses by building more secretory cells and increasing mucus production. The same process occurs in individuals exposed to high levels of air pollution, Christenson said.

Still a hypothesis

While high numbers of goblet and club cells, laden with ACE2 receptors, may explain why smokers fall severely ill of COVID-19, the exact relationship between ACE2 and disease prognosis "remains to be demonstrated," Sheltzer and Smith noted.

Smoking is associated with many comorbidities — multiple medical conditions that appear simultaneously — including emphysema and compromised immune function, which likely exacerbate COVID-19 infections, they wrote. In general, smokers already face a heightened risk of catching viral infections, likely due to their having depressed immune systems , tissue damage and chronic inflammation in the respiratory tracts, Christenson added.

High ACE2 levels may not be unique to smokers, but instead may be common among people with lung conditions, in general, the authors noted. The team did analyze tissue samples from patients with asthma and the inflammatory disease sarcoidosis, however, and these did not contain abnormal quantities of the receptor.

To tease out how ACE2 levels relate to lung disease, in general, future research could focus on patients with chronic obstructive pulmonary disease ( COPD ), bronchitis, pneumonia or lung diseases triggered by bacterial, viral or fungal infections, Alqahtani said. If they also have elevated levels of ACE2 receptors on their cells, that could help clarify whether cigarette smoke poses a singular threat to COVID-19 patients, or if other lung conditions present risks for the same reason.

If smoking does prove uniquely dangerous for COVID-19 patients, however, the study does offer a potential solution.

"We show that former smokers have lower levels of ACE2 than current smokers" — about 30% lower, Sheltzer said. "It’s conceivable that quitting smoking could be beneficial to decrease COVID-19 susceptibility, for multiple reasons."

"Indeed, it also allows us to consider campaigns and programs aimed at helping smokers quit as a preventative strategy going forward," Alqahtani added.