There are multiple known risk factors that increase the risk of severe illness from a SARS-CoV-2 infection; for example, increased age, obesity, and heart conditions. Currently, smoking is also associated with increased risk of severe COVID-19, but it is unclear how cigarette smoke exposure affects SARS-CoV-2 airway cell infection. Now, UCLA researchers, using a model of airway tissue created from human stem cells, have pinpointed how smoking cigarettes causes more severe infection by SARS-CoV-2 in the airways of the lungs.
The group found that direct cigarette smoke exposure increases the number of SARS-CoV-2 infected cells, SARS-CoV-2 infection inhibits the airway basal stem cell repair response, and that cigarette smoke reduces innate immune responses with SARS-CoV-2 infection. The data will help researchers better understand COVID-19 risks for smokers and could inform the development of new therapeutic strategies to help reduce smokers’ chances of developing severe disease.
The study is published as a Brief Report in Cell Stem Cell in a paper titled, “Direct exposure to SARS-CoV-2 and cigarette smoke increases infection severity and alters the stem cell-derived airway repair response.”
Cigarette smoking is one of the most common causes of lung diseases, including lung cancer and chronic obstructive pulmonary disease, and most demographic studies of COVID-19 patients have indicated that current smokers are at increased risk of severe infection and death. But the reasons why have not been entirely clear.
To help understand how smoking affects SARS-CoV-2 infection on a cellular and molecular level, Brigitte Gomperts, MD, professor, pediatrics; pulmonary medicine at the Broad Stem Cell Research Center at UCLA, partnered with co-senior authors Vaithilingaraja Arumugaswami, PhD, an associate professor of molecular and medical pharmacology, and Kathrin Plath, PhD, a professor of biological chemistry—both at UCLA, to recreate what happens when the airways of a current smoker are infected with SARS-CoV-2.
The researchers directly exposed air-liquid interface cultures derived from primary human nonsmoker airway basal stem cells (ABSCs) to short-term cigarette smoke and then infected them with SARS-CoV-2.
The air-liquid interface cultures used in the study were grown from airway stem cells taken from the lungs of five young, healthy, nonsmoking tissue donors. To replicate the effects of smoking, the researchers exposed these airway cultures to cigarette smoke for three minutes per day over four days.
“Our model replicates the upper part of the airways, which is the first place the virus hits,” said Gomperts. “This is the part that produces mucus to trap viruses, bacteria, and toxins and contains cells with finger-like projections that beat that mucus up and out of the body.”
“This type of model has been used to study lung diseases for over a decade and has been shown to mimic the changes in the airway that you would see in a person who currently smokes,” said Gomperts.
Next, the group infected the cultures exposed to cigarette smoke—along with identical cultures that had not been exposed—with live SARS-CoV-2 virus and the two groups were compared. In the models exposed to smoke, the researchers saw between two and three times more infected cells.
They found an increase in the number of infected airway cells after cigarette smoke exposure with a lack of ABSC proliferation.
Digging further, the researchers determined that smoking resulted in more severe SARS-CoV-2 infection, at least in part, by blocking the activity of immune system messenger proteins called interferons. The authors wrote that single cell profiling of the cultures showed that the normal interferon response was reduced after cigarette smoke exposure with infection.
Interferons play a critical role in the body’s early immune response by triggering infected cells to produce proteins to attack the virus, summoning additional support from the immune system, and alerting uninfected cells to prepare to fight the virus. Cigarette smoke is known to reduce the interferon response in the airways.
They added that treatment of cigarette smoke-exposed ALI cultures with Interferon β-1 abrogated the viral infection, “suggesting one potential mechanism for more severe viral infection.”
“If you think of the airways like the high walls that protect a castle, smoking cigarettes is like creating holes in these walls,” Gomperts said. “Smoking reduces the natural defenses and that allows the virus to set in.”
