The vast majority of people infected with the omicron variant of SARS-CoV-2 will experience mild cold-like symptoms, moderate flu-like symptoms or no symptoms at all, but the virus is so contagious that it still penetrates deep into lung tissue , in 2022 alone, thousands of people in the United States will suffer from serious illness and death. Researchers at the University of North Carolina at Chapel Hill have revealed the biology of how disease progression occurs and why some people with asthma are less susceptible to severe COVID.
This study was published in Proceedings of the National Academy of Sciences, illustrating the importance of a well-known cytokine called interleukin 13 (IL-13) in protecting cells from SARS-CoV-2 infection, which helps explain why people with allergic asthma despite with chronic disease but better than the general population. Lung condition. This is not the case for people with other medical conditions, such as chronic obstructive pulmonary disease (COPD) or emphysema, who are at very high risk for severe COVID.
“We know that people with allergic asthma appear to be more immune to severe disease, and there must be a biological mechanism for this,” said senior author Camille Ehre, PhD, assistant professor of pediatrics at the UNC School of Medicine and member of the UNC Marsico Lung. graduate School. “Our research team found many remarkable cellular changes, particularly due to IL-13, leading us to conclude that IL-13 plays a unique role in defense against SARS-CoV-2 infection in certain patient populations. “
While cytokines like IL-13 cannot be used as therapy because they trigger inflammation, understanding the natural molecular pathways that cells use to protect themselves from pathogens is important because 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 as the pandemic continues, epidemiologists have found that people with allergic asthma are less likely to develop severe disease.
“These are asthmatics caused by allergens like mold, pollen and dander,” said Ehre, who is also a member of the UNC Children’s Research Institute. “To find out why they were less sensitive, we investigated specific cellular mechanisms in primary human airway epithelial cell cultures.”
The experiments were led by co-first authors Cameron Morrison, a medical student in Ehre’s lab, and Caitlin Edwards, a research associate and MPH student in the lab of Ralph Baric, the Kenan Professor of Epidemiology at the UNC Gillings School. Professor of Global Public Health and Department of Microbiology and Immunology, University of North Carolina School of Medicine.
Genetic analysis of human airway cell cultures infected with SARS-CoV-2 found that expression of the human protein ACE2 determines which cell types are infected and the amount of virus (also known as “viral load”) found in that cell population. ”).”)
The scientists then used electron microscopy (EM) to identify massive viral efflux from infected ciliated cells, which are tasked with moving mucus along the surface of the airways. EM also revealed severe cytopathies—changes inside human cells caused by viral infection. These changes eventually lead to the shedding of ciliated cells (filled with virus particles) from the surface of the airways.
“This shedding provides a large viral reservoir for the spread and spread of SARS-CoV-2,” Ehre said. “It also appears to increase the likelihood that infected cells will migrate deeper into the lung tissue.”
Further experiments on infected airway cells showed that a major mucus protein called MUC5AC was depleted within the cells, likely because these proteins are secreted in an attempt to trap invading viruses. But the viral load kept increasing as the cells responsible for producing MUC5AC were overwhelmed by rampant viral infection.
Researchers know from epidemiological studies that people with allergic asthma — known to overproduce MUC5AC — less susceptible to severe COVID. Ehre and colleagues also know that the cytokine IL-13 increases the secretion of MUC5AC in the lungs when asthmatics are exposed to allergens.
The scientists decided to mimic the asthmatic airways by treating human airway cells with IL-13. They then measured viral titers, viral mRNA, rate of shedding of infected cells, and total number of infected cells. Each is significantly reduced. They found that this was true even when the mucus was removed from the cultures, suggesting that other factors are involved in the protective effect of IL-13 against SARS-CoV-2.
Bulk RNA-sequencing analysis showed that IL-13 upregulates genes that control glycoprotein synthesis, ion transport and antiviral processes—all important in airway immune defense. They also showed that IL-13 decreased the expression of the viral receptor ACE2 and reduced the amount of virus within cells and the spread of virus between cells.
Taken together, these findings suggest that IL-13 significantly affects viral entry, intracellular replication, and viral spread, thereby limiting the ability of the virus to penetrate deep into the airways to cause severe disease.
“We think this study further demonstrates the importance of treating SARS-CoV-2 infection as early as possible,” Ehre said. “It shows how important specific mechanisms involving ACE2 and IL-13 are as we do our best to protect patients from serious infections.”
Additional authors on the PNAS paper are UNC-Chapel Hill’s Kendall Shaffer, Kenza Araba, Jason Wykoff, Danielle Williams, Takanori Asakura, Hong Dang, Lisa Morton, Rodney Gilmore, Wanda O’Neal, and Ric Boucher.
This research was funded by the National Institutes of Health and Vertex Pharmaceuticals.