Common respiratory virus manipulates immune genes to protect itself
Findings could lead to better therapies for respiratory syncytial virus infection

Date:
October 12, 2021
Source:
Washington University School of Medicine
Summary:
Researchers have discovered that the viral protein NS1 from
respiratory syncytial virus (RSV) alters the activity of immune
genes, sabotaging the immune response to RSV infection.



FULL STORY ========================================================================== Nearly everyone gets infected with respiratory syncytial virus (RSV)
repeatedly over the course of a lifetime, starting in childhood. Most
times, people fight off the virus handily and only end up with a mild
cold. But some people -- most often young children experiencing their
first infection or older adults whose immunity has waned -- develop
pneumonia or bronchiolitis, serious lung infections that can lead to hospitalization and sometimes death.


========================================================================== Researchers at Washington University School of Medicine in St. Louis have figured out how the virus undermines the body's defenses, a step toward understanding why the virus is capable of causing serious illness in
vulnerable populations. They discovered that the virus produces a protein
-- called nonstructural protein 1, or NS1 -- that slips inside the nucleus
and alters the activity of immune genes, sabotaging the immune response.

The findings, published Oct. 12 in Cell Reports, point toward new
strategies to prevent or treat RSV infection, and may even provide clues
to why severe cases of RSV put people at elevated risk of developing
asthma.

"RSV is a significant health burden. It leads to thousands of
hospitalizations and a significant number of deaths in the U.S. every
year, and there aren't many effective therapies or any vaccines
currently available for it," said co- senior author Daisy W. Leung,
PhD, an associate professor of medicine, of biochemistry & molecular biophysics, and of pathology & immunology. "NS1 is an important part of
the reason RSV is capable of causing disease. Not only does the protein interfere with the immune response, it is also important for viral
replication. I think the work that we describe in this paper provides
a basis for targeting NS1 therapeutically or for vaccine development."
RSV is a very common virus. Every year in the U.S., about 58,000 children
under age 5 are hospitalized due to RSV infection, and 100 to 500 infected children die. Children who survive a serious case of RSV are 30% to 40%
more likely than the general population to develop recurrent wheezing
or asthma. The virus also kills about 14,000 older adults every year.

Before this study, RSV researchers already had NS1 on their radars as one
of the weapons used by the virus to counter the body's defenses. In 2017,
Leung published a paper in Nature Microbiology identifying the precise
part of the protein involved in undermining the immune response. But it
wasn't clear how the protein was doing so.

To find out, co-first author Jingjing Pei, PhD, then a postdoctoral
researcher in Leung's lab, infected cells taken from a person's
respiratory tract with RSV. Then, she used an antibody against NS1 that
the Leung lab and collaborators on the study developed to track where
the protein went inside the cells. She found that while the virus genome
and other viral proteins stayed in the main part of the cell and produced
more copies of the virus, NS1 sneaked into the nucleus.

Further experiments by co-first author Nina R. Beri, PhD, revealed what
NS1 was doing in the nucleus: sabotaging the cell's antiviral efforts
by altering the expression of its immune genes. Beri, who has since
graduated, conducted the experiments as a graduate student in the lab
of co-senior author Jacqueline E.

Payton, MD, PhD, an assistant professor of pathology & immunology.

"NS1 wasn't just floating around the nucleus, it was interacting with the proteins that regulate gene expression," Payton said. "The group of genes
most affected were the immune-response genes whose expression gets turned
on really high when a cell is infected by a virus. It was binding right
at the spots on the genome that control expression -- the same ones that
you'd expect if it were trying to interfere with the immune response."
By illuminating the details of how NS1 manipulates gene expression,
this study provides crucial data that could aid efforts to target the
protein for drug or vaccine development. It may even provide a clue to
the link between RSV and asthma. The key, Payton suggested, may lie
in the epigenome, the pattern of chemical units attached to DNA that
influence gene expression.

"Once a cell -- any cell, not just an immune cell -- encounters an
infection, its epigenome changes and primes it to be able to respond
more quickly the next time it encounters an infection," Payton said. "My
theory is that NS1 may alter the epigenome in susceptible patients
such that the next time they encounter RSV -- or maybe even just dust
or cat dander -- they have an aberrant inflammatory response that is
damaging rather than protective. That is an idea we are exploring now." ========================================================================== Story Source: Materials provided by
Washington_University_School_of_Medicine. Original written by Tamara
Bhandari. Note: Content may be edited for style and length.


========================================================================== Journal Reference:
1. Pei J, Beri NR, Zou AJ, Hubel P, Dorando HK, Bergant V, Andrews
RD, Pan
J, Andrews JM, Sheehan KCF, Pichlmair A, Amarasinghe GK, Brody SL,
Payton JE, Leung DW. Nuclear-localized human respiratory syncytial
virus NS1 protein modulates host gene transcription. Cell Reports,
Oct. 12, 2021 DOI: 10.1016/j.celrep.2021.109803 ==========================================================================

Link to news story: https://www.sciencedaily.com/releases/2021/10/211012112213.htm

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