Human norovirus strains differ in sensitivity to the body's first line
of defense
Date:
September 10, 2020
Source:
Baylor College of Medicine
Summary:
Human norovirus strains differ in sensitivity to interferon,
one of the body's first line of defense.
FULL STORY ========================================================================== Interferon (IFN) responses are one of the first defenses the body mounts against viral infections, and research has shown that it plays a role controlling viral replication. But when researchers at Baylor College
of Medicine investigated whether IFN restricted human norovirus (HuNoV) infection in human intestinal enteroids (HIEs), a cultivation system
that recapitulates many of the characteristics of the human infection,
they unexpectedly discovered that endogenous IFN responses by HIEs
restricted growth of HuNoV strain GII.3, but not of GII.4, the most
common strain worldwide.
==========================================================================
The findings, published in the Proceedings of the National Academy of
Sciences, highlight the importance of considering strain differences
when studying HuNoV biology and designing therapies.
"HuNoVs cause the majority of the cases of viral gastroenteritis in the
world and bring about significant mortality in all age groups; yet, there
are still no vaccines or other approved therapeutic strategies available,"
said first author Shih-Ching Lin, a graduate student in the laboratory
of Dr. Mary Estes at Baylor. "In-depth studies of how virus and host
interact have been possible only recently thanks to the development of
several laboratory cultivation systems. In this study, we worked with
HIEs to investigate their response to HuNoV infection and how it affects
viral replication." Novel insights into the interplay between HuNoV and
HIEs The researchers infected HIEs with HuNoV strain GII.3 or pandemic
strain GII.4 and determined which HIE genes were activated as a result.
"We discovered that both strains preferentially triggered a type III
IFN response, including activation of a number of IFN-stimulated genes,
as well as increases in a subset of long non-coding RNAs. Changes in long non-coding RNAs, which are known to regulate gene expression, had never
been reported before for gastrointestinal virus infections," Lin said.
Next, Lin, Estes and their colleagues studied the effect of IFN on the replication of HuNoV. Adding IFN to the cultures reduced replication
of both strains, suggesting that IFN may have value as therapeutics
for HuNoV infections. This could be important for chronically infected immunocompromised patients who can suffer with diarrhea for years.
To obtain insights into the genes of the IFN pathway that contribute to
the antiviral response to HuNoV, the researchers knocked out several of
these genes in HIE cultures, infected them with strain GII.3 or GII.4
and measured the rate of viral proliferation.
"We expected that the absence of IFN responses by HIEs would promote
viral replication in both strains. It was surprising and very exciting
to find significant strain differences," Lin said.
"We saw that only strain GII.3 was able to spread and multiply more
when HIEs could not activate IFN responses. Replication of GII.4,
on the other hand, was not enhanced," said Estes, Cullen Foundation
Endowed Chair and Distinguished Service Professor of molecular virology
and microbiology at Baylor. Estes also is a member of the Dan L Duncan Comprehensive Cancer Center. "It was exciting to see the GII.3 strain proliferate and spread in the cultures as we had never seen it before."
"The strain-specific sensitivities of innate IFN responses to HuNoV
replication we observed provide a potential explanation for why GII.4 infections are more widespread and become pandemic," Lin said. "Our
findings also show the importance of keeping potential strain differences
in mind when studying the biology of HuNoV and developing therapies. Our
new genetically modified HIE cultures also will be useful tools for
studying innate immune responses to other viral or microbial pathogens."
========================================================================== Story Source: Materials provided by Baylor_College_of_Medicine. Note:
Content may be edited for style and length.
========================================================================== Journal Reference:
1. Shih-Ching Lin, Lin Qu, Khalil Ettayebi, Sue E. Crawford, Sarah
E. Blutt,
Matthew J. Robertson, Xi-Lei Zeng, Victoria R. Tenge,
B. Vijayalakshmi Ayyar, Umesh C. Karandikar, Xiaomin Yu, Cristian
Coarfa, Robert L. Atmar, Sasirekha Ramani, Mary K. Estes. Human
norovirus exhibits strain-specific sensitivity to host interferon
pathways in human intestinal enteroids.
Proceedings of the National Academy of Sciences, 2020; 202010834
DOI: 10.1073/pnas.2010834117 ==========================================================================
Link to news story:
https://www.sciencedaily.com/releases/2020/09/200910110850.htm
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