Researchers have revealed biological reasons for how disease progression happens and why a certain population of asthma patients are less susceptible to severe COVID.
This research, published in PNAS, shows the importance of the well-known cytokine interleukin-13 (IL-13) in protecting cells against SARS-CoV-2, something which helps explain why people with allergic asthma fare better than the general population despite having a chronic lung condition. However, the same cannot be said for individuals with other diseases, 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 bio-mechanistic reason why people with allergic asthma seemed more protected from severe disease,” said Assistant Professor Camille Ehre, PhD, senior author of the paper. “Our research team discovered a number of significant cellular changes, particularly due to IL-13, leading us to conclude that IL-13 plays a unique role in defence against SARS-CoV-2 infection in certain patient populations.”
Although cytokines like IL-13 cannot be used as therapies because they trigger inflammation, it is important to understand natural molecular pathways that cells use to protect themselves from pathogen invasion, as these studies have the potential to reveal new therapeutic targets.
Many health factors increase a person’s risk of severe COVID, but during the pandemic, epidemiologists found that people with allergic asthma were less susceptible to severe disease.
“These are patients with asthma caused by allergens, such as mould, pollen, and dander,” said A/Prof Ehre. “To find out why they are less susceptible, we investigated specific cellular mechanisms in primary human airway epithelial cell cultures.”
Genetic analysis human airway cell cultures infected with SARS-CoV-2 revealed that the expression of ACE2 governed which cell types were infected and their viral load.
Electron microscopy (EM) identified an intense exodus of virus from infected ciliated cells, which move mucus along the airway surface. EM also revealed severe cytopathogenesis – changes inside human cells due to viral infection. And these changes culminating in ciliated cells (packed with virions) shedding away from the airway surface.
“This shedding is what provides a large viral reservoir for spread and transmission of SARS-CoV-2,” A/Prof Ehre said. “It also seems to increase the potential for infected cells to relocate to deeper lung tissue.”
Further experiments on infected airway cells revealed that a major mucus protein called MUC5AC was depleted inside cells, likely because the proteins were secreted to try to trap invading viruses. But the virus load kept increasing because the cells tasked with producing MUC5AC were overwhelmed in the face of a rampant viral infection.
The researchers knew from epidemiological studies that allergic asthma patients—known to overproduce MUC5AC—were less susceptible to severe COVID. A/Prof Ehre and colleagues also knew the cytokine IL-13 increased MUC5AC secretion in the lungs when asthma patients faced an allergen.
The scientists decided to mimic asthmatic airways by treating human airway cells with IL-13. They then measured viral titres, viral mRNA, the rate of infected cell shedding, and the overall number of infected cells. Each one was significantly decreased. They found this remained true even when mucus was removed from the cultures, suggesting other factors were involved in the protective effects of IL-13 against SARS-CoV-2.
Bulk RNA-sequencing analyses revealed that IL-13 upregulated genes that control glycoprotein synthesis, ion transport, and antiviral processes – all of which are important in airway immune defence. They also showed that IL-13 reduced the expression of the viral receptor, ACE2, as well as reducing the amount of virus inside cells and cell-to-cell viral transmission.
Taken together, these findings indicate that IL-13 significantly affected viral entry into cells, replication inside cells, and spread of virus, thus limiting the virus’s ability to find its way deeper into the airways to trigger severe disease.
“We think this research further shows how important it is to treat SARS-CoV-2 infection as early as possible,” A/Prof Ehre said. “And it shows just how important specific mechanisms involving ACE2 and IL-13 are, as we try our best to protect patients from developing severe infections.”
