Asthma is a lung disease that causes sporadic respiratory distress. It often begins in childhood, although it can also appear in adults and affects people of all ages. There is currently no cure, but treatment can help control symptoms. The disease is caused by inflammation and narrowing of the bronchi (ducts through which air enters and leaves the lungs).
SARS-CoV-2 is the third coronavirus outbreak affecting the human population since the beginning of the 21st century and was preceded by SARS-CoV in 2002 and MERS-CoV in 2012. Clinical symptoms of COVID-19 vary widely among infected people, from asymptomatic illness to severe respiratory illness and even death in almost 2% of cases. The vast majority of people infected with the Ómicron variant experience mild cold-like symptoms, moderate flu-like symptoms or no symptoms, but this does not mean that the pandemic is about to end, as new variants are latent.
Now, researchers at the University of North Carolina (UNC) at Chapel Hill have revealed in a recent study the biological reasons for how the disease progression occurs and why the population of asthma patients is less susceptible to Severe COVID-19.
The scientists turned their conclusions into a paper published in the Proceedings of the National Academy of Sciences. They reveal the importance of a well-known cytokine called interleukin-13 (IL-13) in protecting cells against SARS-CoV-2, which helps explain the mystery of why people with allergic asthma fare better than the general population despite having a chronic lung condition. They could not prove the same for those with other ailments, such as chronic obstructive pulmonary disease (COPD) or emphysema, who are at very high risk of severe COVID.
“We knew there had to be a biomechanical reason why people with allergic asthma seemed more protected from serious illness,” explained lead author Camille Ehre, assistant professor of pediatrics at the University of North Carolina School of Medicine. Our research team discovered a number of significant cellular changes, particularly due to IL-13, which led us to conclude that it plays a unique role in defending against SARS-CoV-2 infection in certain patient populations.”
Although cytokines such as IL-13 cannot be used as therapies because they trigger inflammation, it is important to understand the natural molecular pathways that cells use to protect themselves from pathogen invasion, as these studies have the potential to reveal new therapeutic targets.
There are many health factors that increase a person's risk of severe COVID, including chronic lung diseases such as COPD, but during the pandemic, epidemiologists found that subjects with allergic asthma were less susceptible to serious illness.
“These are patients with asthma caused by allergens, such as mold, pollen and dandruff,” explained Ehre, who is also a member of the UNC Children's Research Institute. To find out why they are less susceptible, we investigated specific cellular mechanisms in primary cultures of human airway epithelial cells.”
The researchers used genetic analysis of cultures of human airway cells infected with SARS-CoV-2 to conclude that expression of the human ACE2 protein governed which types of cells were infected and the amount of virus found in this cell population (also known as viral load).
The scientists then used electron microscopy to identify an intense exodus of virus from infected hair cells, which are responsible for moving mucus along the surface of the airways. MS also revealed changes within human cells due to a viral infection. And these mutations culminate in hair cells that break off the surface of the airways. “This detachment is what provides a large viral reservoir for the spread and transmission of SARS-CoV-2,” Ehre explained. It also seems to increase the potential for infected cells to move into deeper lung tissue.”
Delving into the investigation, the specialists detected that infected airway cells revealed that an important mucous protein called MUC5AC was depleted inside them, probably because the proteins were secreted to try to trap invading viruses. But the virus load continued to increase because the cells responsible for producing MUC5AC were overwhelmed by a rampant viral infection.
Scientists already knew from epidemiological studies that patients with allergic asthma, who are known to overproduce MUC5AC, were less susceptible to severe COVID. Ehre and his colleagues also knew that the cytokine IL-13 increased MUC5AC secretion in the lungs when asthma patients were confronted with an allergen. So they decided to mimic the respiratory tract of asthmatics by treating others with IL-13.
They then measured viral titers, viral mRNA, clearance rate, and total number of infected cells. Both were significantly reduced. They found that this was still true even when mucus was cleared from cultures, suggesting that other factors were involved in the protective effects of IL-13 against SARS-CoV-2.
RNA sequencing analysis revealed that IL-13 upregulated genes that control antiviral processes, important in airway immune defense. They also demonstrated that IL-13 reduced the amount of virus within cells and cell-to-cell viral transmission.
Taken together, these findings indicate that IL-13 significantly affected viral entry into cells, replication within cells, and spread of the virus, limiting the virus's ability to find its deepest path into the airways and trigger serious disease. “We believe that this research shows even more how important it is to treat SARS-CoV-2 infection as soon as possible,” Ehre concluded.
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