Dominant SARS-CoV-2 Alpha variant evolved to evade our innate immune
system

Date:
December 23, 2021
Source:
University College London
Summary:
The SARS-CoV-2 Alpha (B.1.1.7) variant mutated to evade our
'innate immune system', helping establish it as the world's first
'Variant of Concern', a new study finds.



FULL STORY ==========================================================================
The SARS-CoV-2 Alpha (B.1.1.7) variant mutated to evade our 'innate
immune system', helping establish it as the world's first 'Variant of
Concern', finds a new study led by researchers at UCL and the Quantitative Biosciences Institute, University of California San Francisco.


========================================================================== Published in Nature, the study shows the Alpha variant, first identified
in the UK, evolved to make more of its 'antagonism proteins' that nullify
the body's first line of defence, known as the 'innate immune system'.

Every cell in the nose, throat and lungs (airways) have a network of
sensors that detect incoming viruses. When this happens the cells produce
the protein interferon, which acts like a 'burglar alarm' and orchestrates
a blanket anti- viral response, across both non-immune and immune cells
(T cells and antibodies) to avert infection. But antagonism proteins
can help the virus to evade these sensors.

This novel discovery is the first to identify evolution of enhanced
antagonism protein expression in anyvirus and the first to implicate
mutations in SARS- CoV-2 that increase infectiousness but do not involve
the 'spike' protein Scientists say the breakthrough findings provide
a powerful insight into how SARS-CoV-2 is evolving, and offer a fresh
clue to help identify new and emerging Variants of Concern, which are
both highly transmissible and infectious.

Co-first author Dr Lucy Thorne (UCL Division of Infection & Immunity)
said: "We wanted to know what made the SARS-CoV-2 Alpha variant
special. How had it evolved from the first wave strain identified in
Wuhan, China, and what features did it have that allowed it to spread
around the world and become the first variant of concern?


==========================================================================
"We found that that the SARS-CoV-2 Alpha variant had adapted to avoid triggering our defensive frontline innate immune response much better than
the first wave viruses. We discovered it does this by making more of the
virus proteins that can disable the innate immune system. These proteins
are called N, Orf6 and Orf9b and are known as innate immune antagonists.

"By mutating to evade our innate immune system, the Alpha variant can
replicate under the radar in the early stages of infection, which we think significantly increases its chances of infecting a person when it lands
in their nose, throat or lungs. For a virus this is a resounding success, enabling it to more efficiently spread from person to person." For the
study, researchers added samples of Alpha (B.1.1.7 lineage) to lab-
grown lung cells -- to mimic the cells infected by the virus in the body.

Scientists then measured how much the virus grew and assessed whether
the innate immune system was activated (or to what degree) by measuring
the amount of interferon produced.

Researchers observed that the levels of interferon produced during
Alpha infection were far lower than all earlier SARS-CoV-2 variants,
which had principally seen mutations to the 'spike' protein.

To pinpoint exactly why Alpha was compromising the innate immune system, collaborators at the Quantitative Biosciences Institute (QBI), including
co- senior author and director of QBI Nevan Krogan and co-first authors
Mehdi Bouhaddou and Lorena Zuliani-Alvarez, looked at how the proteins expressed in Alpha differed from previous variants. By measuring all of
the proteins and all of the RNA in infected cells, they found antagonism proteins N, Orf6 and Orf9b, which are present in all coronaviruses
and whose function is to dampen down cell responses, were 'dialled up'
in the Alpha variant.



========================================================================== Researchers believe this increase in antagonism proteins is the result
of numerous mutations in the regulatory regions of SARS-CoV-2, which
control protein expression levels.

Commenting on the findings, co-senior author Professor Greg Towers (UCL Division of Infection & Immunity), said: "We have never seen anything
like this before; we know viruses adapt and we expect to see the proteins adapting so they work better in humans. But Alpha is using its antagonism proteins, that help evade detection a little bit, and cranking up how
much it makes. That is unique.

"The real value of our discovery is showing how this incredible virus
evolved from the initial SARS-CoV-2 strain, and it also helps us
understand how our protective innate immunity works." In preliminary
research, the team has identified that someof the mutations to the
regulatory regions of SARS-CoV-2 found in Alpha are present in the
subsequent Variants of Concern, Delta and Omicron, but it is believed
these variants succeeded primarily due to mutations in the spike protein.

Co-first author Dr Ann-Kathrin Reuschl (UCL Division of Infection &
Immunity) added: "It will be fascinating to see how the other variants,
such as Delta and Omicron, perform comparatively in our lung epithelial systems. Whether the viruses rely on similar approaches to innate
antagonism or have evolved distinct strategies to evade the immune
defences, will teach us not only about the viruses themselves but also
about human biology." Co-senior author Professor Clare Jolly (UCL
Division of Infection & Immunity) added: "It's fascinating to watch a
virus evolve in real time -- we expect it to continue to evolve and we
hope our work will help to understand the next round of variants too." ========================================================================== Story Source: Materials provided by University_College_London. Note:
Content may be edited for style and length.


========================================================================== Journal Reference:
1. Lucy G. Thorne, Mehdi Bouhaddou, Ann-Kathrin Reuschl, Lorena
Zuliani-
Alvarez, Ben Polacco, Adrian Pelin, Jyoti Batra, Matthew
V. X. Whelan, Myra Hosmillo, Andrea Fossati, Roberta Ragazzini,
Irwin Jungreis, Manisha Ummadi, Ajda Rojc, Jane Turner, Marie
L. Bischof, Kirsten Obernier, Hannes Braberg, Margaret Soucheray,
Alicia Richards, Kuei-Ho Chen, Bhavya Harjai, Danish Memon,
Joseph Hiatt, Romel Rosales, Briana L. McGovern, Aminu Jahun,
Jacqueline M. Fabius, Kris White, Ian G. Goodfellow, Yasu
Takeuchi, Paola Bonfanti, Kevan Shokat, Natalia Jura, Klim Verba,
Mahdad Noursadeghi, Pedro Beltrao, Manolis Kellis, Danielle
L. Swaney, Adolfo Garci'a-Sastre, Clare Jolly, Greg J. Towers,
Nevan J. Krogan. Evolution of enhanced innate immune evasion by
SARS-CoV-2. Nature, 2021; DOI: 10.1038/s41586-021-04352-y ==========================================================================

Link to news story: https://www.sciencedaily.com/releases/2021/12/211223113047.htm

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