Nature's latest research finds weaknesses in the coronavirus!

After three years of infection, lockdown, and vaccination, we know more about the SARS-CoV-2 virus that causes COVID-19, but we still have a lot to know
.
For example, why are some variants weaker than others? Why does the Omicron variant spread so quickly and make people less sick? Are new viral mutations exposing us to new risks, or are we closer to the end of the pandemic? Are there more effective vaccines to be developed?

A new study led by an international team of researchers may provide some answers
.
In a paper published online in the journal Nature, they identified mutations that helped Omicron dodge previous immunity and suggested that a previously undiscovered viral protein, known as nsp6, may be a key factor
in the variant's lower pathogenic potential or pathogenicity.
A piece of content containing some of the paper's early results made international headlines last October when a series of false reports misinterpreted the paper's findings
.
Mohsan Saeed, a senior author of the study and a virologist at Boston University, said their study could have a significant positive impact and could help provide new targets for vaccines and treatments
.

Saeed, assistant professor of biochemistry at the BU Chobanian & Avedisian School of Medicine, said: "This is an important piece of work that shows that the spike protein contributes little to the low pathogenicity of Omicron, while mutations in another protein, NSP6, play a crucial role
.
This provides an exciting new concept for our future vaccines and therapeutics – and if we know how to weaken the virus, we can better fight it
.
”

Jonathan Li, an associate professor at the Royal College of Medicine and one of the study's co-authors, said that while much research has focused on the spike protein of SARS-CoV-2, little is known about the rest of its genome
.

"The non-spiked part of the viral genome has not been adequately studied
.
Studies like this are helping us understand which parts of the viral genome influence pathogenesis, which we still don't know," Li said, noting that it's not clear, for example, why the Omicron BA.
5 subvariant easily beats the BA.
4 version, even though the two variants share the same spike sequence
.
Dr.
Saeed's research shows us the relative impact
of different SARS-CoV-2 gene fragments on disease severity.
This type of research not only has the potential to predict which variants may lead to new waves of infection, but also to identify targets for new therapies against COVID-19
.
”

Omicron's weakness

Saeed's lab has been studying SARS-CoV-2 since the outbreak, studying the first strain of coronavirus detected from a patient in the United States, Washington or wild-type isolate.

When the Omicron variant appeared at the end of 2021, it soon became clear that it spread faster
than previous variants.
However, Omicron is also weaker, or weaker—less lethal
.
Saeed wanted to know why
.

"The disease it causes is relatively less severe," Saeed said, "and what's so special about Omicron that it causes milder disease?" That's why this project started – we wanted to investigate this
.
”

In a safety lab at Boston University's National Laboratory for Emerging Infectious Diseases (NEIDL), researchers first studied the virus's spike protein, a molecule that helps SARS-CoV-2 invade cells and start infections, and is also used in most vaccines
.
One of the reasons for focusing on this mutation is that scientists have determined that it is the main difference between the Omicron virus and the original virus: most mutations are concentrated on
this one protein.

"The first experiment we did was to put Omicron's spike into
a wild-type virus," Saeed said.
This creates a chimeric recombinant virus—a modified virus that contains different segments of the virus's genes—which they call Omi-S, a version of the original virus that contains the Omicron protein
.
"The idea is that if spike is the cause of the Omicron virus decay, then the Omi-S and Omicron viruses should cause similarly mild illness
.
"

In some ways, he added, nature shows us the way
forward.

"The disease caused by Omicron is relatively mild, and nature has told us how to weaken the virus, how to make it weaker
," Saeed said.
Weakening the virus has long been used by scientists to fight deadly diseases, from polio to yellow fever — as early as the 19th century, Louis Pasteur experimented with live attenuated vaccines
with weaker versions of the virus.
We can learn from
nature.
If we can unravel or decode nature's pathways, we can help us make vaccines
.
”

Functional gain and mortality

Unlike in Pasteur's time, today's researchers have to follow very strict protocols
to modify any virus.
If they find any signs that the virus is getting stronger rather than weaker — so-called enhanced functionality — they are asked to pause research and eradicate the virus to avoid the possibility of
more dangerous viruses spreading to the public.

"The tradition in the field is that if you're going to generate a chimeric virus, you have to compare
it to a backbone virus.
In our case, that was the Washington isolate.

Think of it this way: Of the roughly 30 proteins, one comes from Omicron and all the others come from Washington isolates
.
”

In this case, the chimeric virus is weakened and remains that way
throughout the study.
When the researchers compared Omicron, Washington and Omi-S in cells cultured in petri dishes, Saeed said, "We found that chimeric viruses are weaker
than wild-type viruses.
"

But it's still not as weak as Omicron, suggesting that it's not just the spike protein that is responsible for the variant's relative lack of pathogenicity
.

"We found that this protein contributes very little to Omicron's pathogenic ability," Saeed said
.

They also tested the three variants of the virus — modified into mice that were more susceptible to disease — in bioengineered animal models — and found the same pattern
.

The initial virus killed 100 percent of the infected mice, Omi-S had a mortality rate of 80 percent, and all of the mice survived contact with Omicron
.
When Saeed's research team initially published the results in draft form, they caused some confusion, with some mostly right-wing media outlets mistakenly believing that these percentages meant the virus had the same mortality or fatality rate
in humans.
That's not the case, Saeed says — a point
he and his co-authors clarified in their final paper in Nature.

In fact, the mice used in the study were designed to be highly sensitive to the virus, so researchers could more quickly and efficiently detect its pathogenic potential
.
For example, when infected with the original Washington virus strain, 100 percent of these mice died, but the disease outcome in humans was very different
.
It is estimated that less than 5% of patients infected with the original virus die
as a result.

Not only is the Omi-S version of the virus less lethal to mice than the type of virus that spread from person to person when COVID first hit the United States, but it also has a low fatality rate for rodents because they are bioengineered to be more susceptible to the virus
.

"There is a huge difference in disease manifestations and outcomes between these artificially engineered mice and humans," said Saeed, whose team did all the work in a biosafety cabinet at the
NEIDL Biosafety Level 3 facility.
(To gain access to their labs, fully vaccinated researchers must walk through a series of rooms and interlocking doors, donning multiple layers of protective gear, including astronaut-like clothing and hoods
.
) )

Less studied proteins

After determining that the spike protein was not the only factor in diluting Omicron's potency, the research team set out to look for other possible causes
.
They eventually discovered a different protein: NSP6
.

In addition to the spike protein, SARS-CoV-2 is made up of a bunch of other molecules that help it complete its "toxic effect.
"
At least four (including spikes) are structural proteins that form viral particles
when they come out of infected cells.
The other 16 are non-structural — they help the virus replicate, creating the environment
in the infected cells that the virus needs to replicate itself.
One of the non-structural proteins is NSP6
.
Its job, Saeed says, is to "facilitate the formation of certain vesicles in infected cells, which are factories
for the amplification of the viral genome.
" ”

According to the Nature paper, when they repeated their experiment with a chimeric virus, adding Omicron's NSP6 protein to Omi-S, "we observed a strong decline in viral replication and infection kinetics mimicking Omicron in cell culture, with Omi-S plus NSP6 virus being weaker
.
" There was also a reduction
in bronchial infections that infected the lungs of mice compared to Omi-S.

"For months, the field has been focusing on the impact of
spikes on driving Omicron attenuation.
This study is unique in that it is the first to identify another SARS-CoV-2 protein, NSP6, which, in addition to the spike, contributes to the attenuation of Omicron," said Florian Douam, a co-author of the study and assistant professor of microbiology at Boston University's Jobanian and Avidician School of Medicine
.
"While spike spikes remain important in defining Omicron attenuation, a lot is happening in other, more understudied SARS-CoV-2 proteins, and this study points this
out for the first time.
"

Saeed said the NSP6 protein is also linked
to inflammation.

"When people are infected with SARS-CoV-2, inflammation develops in the lungs, leading to pneumonia and acute respiratory distress syndrome
.
NSP6 seems to have played a role
in this.
I think our study will really provide impetus to study NSP6 and see what other functions it has in viral replication and subsequent lung disease — it's not one of
the proteins that has been studied a lot.
”

Learn about SARS-CoV-2 and reduce its threat

The research team, who will soon begin further research into NSP6, say the latest findings are exciting because they open up a new pathway
to eliminate COVID.
According to Douam, understanding the small genetic differences between variants is critical
to providing new insights into how viruses cause disease.

"By exchanging genetic signatures between two variants with different toxicity, researchers can identify key components
associated with SARS-CoV-2's pathogenic potential," he said.
This research is critical not only because it tells us what the elements that regulate viral toxicity, but also highlights the potential
of these viral elements as important drug targets.
”

(Biocom)

Original:

Spike and nsp6 are key determinants of SARS-CoV-2 Omicron BA.
1 attenuation