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Scientists unveil biological mechanisms of severe COVID

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Newswise – CHAPEL HILL, NC – The vast majority of people infected with the omicron variant of SARS-CoV-2 have mild cold-like symptoms, moderate flu-like symptoms, or no symptoms at all, but the virus is so transmissible that it has yet to spread deep into lung tissue to cause serious illness and death in thousands of people in the United States in 2022 alone. Researchers from the University of North Carolina at Chapel Hill have revealed the biological reasons for disease progression and why a certain population of asthma patients is less susceptible to severe COVID.

This research, published in the Proceedings of the National Academy of Sciences, illustrates 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 fared better than the general population despite a chronic lung condition. The same cannot be said for people with other illnesses, such as chronic obstructive pulmonary disease (COPD) or emphysema, who are at very high risk for severe COVID.

“We knew there had to be a biomechanical reason why people with allergic asthma seemed more protected against serious disease,” said lead author Camille Ehre, PhD, assistant professor of pediatrics at UNC School. of Medicine and a member of UNC Marsico Lung. Institute. “Our research team discovered a number of important cellular changes, particularly due to IL-13, which lead us to conclude that IL-13 plays a unique role in the defense against SARS infection. -CoV-2 in certain patient populations.

Although cytokines like IL-13 cannot be used as therapies because they trigger inflammation, it is important to understand the natural molecular pathways cells use to protect themselves from invading pathogens because these studies have the potential to reveal new therapeutic targets.

There are many health factors that increase the risk of severe COVID, including chronic lung diseases such as COPD, but as the pandemic continued epidemiologists found people with allergic asthma were less likely to contract a serious illness.

“These are asthma patients caused by allergens, such as mold, pollen, and dander,” said Ehre, who is also a fellow at the UNC Children’s Research Institute. “To find out why they are less sensitive, we studied specific cellular mechanisms in primary cultures of human airway epithelial cells.”

The experiments were led by co-first authors Cameron Morrison, a medical student in Ehre’s lab, and Caitlin Edwards, a research assistant and MPH student in the lab of Ralph Baric, PhD, Kenan Distinguished Professor of Epidemiology at the ‘UNC Gillings School of Global Public Health and Professor in the UNC Department of Microbiology and Immunology in the UNC School of Medicine.

Researchers used genetic analysis of cultures of human respiratory tract cells infected with SARS-CoV-2 to find that expression of the human ACE2 protein governed the types of cells infected and the amount of virus found in this population. cellular (also known as “viral load”. . )

The scientists then used electron microscopy (EM) to identify an intense exodus of virus from infected hair cells, which are cells responsible for moving mucus along the surface of the airways. ME also revealed severe cytopathogenesis – changes inside human cells due to viral infection. And these changes result in hair cells (filled with virions) that detach from the surface of the airways.

“This shedding is what provides a large viral reservoir for the spread and transmission of SARS-CoV-2,” Ehre said. “It also appears to increase the potential for infected cells to travel to deeper lung tissue.”

Further experiments on infected airway cells revealed that a major mucus protein called MUC5AC was depleted inside the cells, likely because the proteins were being secreted in an attempt to trap invading viruses. But the viral load kept increasing because the cells responsible for producing MUC5AC were overwhelmed by an endemic viral infection.

Researchers knew from epidemiological studies that allergic asthma patients – 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 challenged with an allergen.

The scientists decided to mimic asthmatic airways by treating human airway cells with IL-13. They then measured viral titers, viral mRNA, shedding rate of infected cells, and total number of infected cells. Each was significantly diminished. They found that this remained true even when the mucus was removed from the cultures, suggesting that other factors were involved in the protective effects of IL-13 against SARS-CoV-2.

Mass RNA sequencing analyzes revealed that IL-13 upregulated genes that control glycoprotein synthesis, ion transport and antiviral processes – all of which are important in airway immune defense. They also showed that IL-13 reduced expression of the viral receptor, ACE2, as well as the amount of virus inside cells and viral cell-to-cell transmission.

Taken together, these results indicate that IL-13 significantly affected viral entry into cells, replication inside cells, and virus spread, thereby limiting the ability of the virus to work its way deeper. in the airways to trigger serious illness.

“We believe this research further shows how important it is to treat SARS-CoV-2 infection as early as possible,” Ehre said. “And it shows how important the specific mechanisms involving ACE2 and IL-13 are, as we do our best to protect patients from developing serious infections.”

Other authors of the PNAS paper are Kendall Shaffer, Kenza Araba, Jason Wykoff, Danielle Williams, Takanori Asakura, Hong Dang, Lisa Morton, Rodney Gilmore, Wanda O’Neal and Ric Boucher, all at UNC-Chapel Hill.

This research was supported by grants from the National Institutes of Health and Vertex Pharmaceuticals.