Why are people with allergic asthma less susceptible to severe COVID?


Date:
March 30, 2022
Source:
University of North Carolina Health Care
Summary:
Scientists show how cells packed with SARS-CoV-2 detach from the
upper airway and spread deep into lungs where severe COVID can take
root. They also discovered how an asthmatic reaction to allergens
battles the virus to hold severe COVID at bay.



FULL STORY ==========================================================================
The vast majority of people infected with the omicron variant of SARS-CoV-
2 experience mild cold-like symptoms, moderate flu-like symptoms, or no symptoms at all, but the virus is so transmissible that it still spread
deep into lung tissue to cause severe disease and death in thousands of
people in the United States in 2022 alone. Researchers at the University
of North Carolina at Chapel Hill revealed biological reasons for how
disease progression happens and why a certain population of asthma
patients are less susceptible to severe COVID.


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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 fair better
than the general population despite having a chronic lung condition. 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 senior author
Camille Ehre, PhD, assistant professor of pediatrics at the UNC School
of Medicine and member of the UNC Marsico Lung Institute. "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
defense 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.

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
went on, epidemiologists found that people with allergic asthma were
less susceptible to severe disease.

"These are patients with asthma caused by allergens, such as mold, pollen,
and dander," said 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 human airway
epithelial cell cultures." The experiments were led by co-first authors Cameron Morrison, a medical student in the Ehre 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 at the UNC School of Medicine.



==========================================================================
The researchers used genetic analysis of human airway cell cultures
infected with SARS-CoV-2 to discover that the expression of the human
protein ACE2 governed which cell types were infected and the amount
of virus found in this cell population (also known as "viral load.")
The scientists then used electron microscopy (EM) to identify an
intense exodus of virus from infected ciliated cells, which are cells
tasked with moving 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," 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 lesssusceptible to severe
COVID. Ehre and colleagues also knew the cytokine IL-13 increased MUC5AC secretion in the lungs when asthma patients faced an allergen.



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The scientists decided to mimic asthmatic airways by treating human
airway cells with IL-13. They then measured viral titers, 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 defense. 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," 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."
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 funded through grants from the National Institutes of
Health and Vertex Pharmaceuticals.


========================================================================== Story Source: Materials provided by
University_of_North_Carolina_Health_Care. Note: Content may be edited
for style and length.


========================================================================== Journal Reference:
1. Cameron B. Morrison, Caitlin E. Edwards, Kendall M. Shaffer,
Kenza C.

Araba, Jason A. Wykoff, Danielle R. Williams, Takanori Asakura, Hong
Dang, Lisa C. Morton, Rodney C. Gilmore, Wanda K. O'Neal, Richard C.

Boucher, Ralph S. Baric, Camille Ehre. SARS-CoV-2 infection of
airway cells causes intense viral and cell shedding, two spreading
mechanisms affected by IL-13. Proceedings of the National Academy
of Sciences, 2022; 119 (16) DOI: 10.1073/pnas.2119680119 ==========================================================================

Link to news story: https://www.sciencedaily.com/releases/2022/03/220330164545.htm

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