Nature discovers a group of cellular receptors

Going a step further, the researchers tested a "decoy" molecule that successfully prevented infection and slowed the progression of the disease in a series of experiments in cell and animal models, a move toward developing prevention and treatments for these diseases.

The findings were published Dec.

Jonathan Abraham, the study's senior author, said that understanding the basic biology of the viral life cycle is critical to finding ways to prevent disease, and building such basic knowledge before an outbreak is critical to preparing for future outbreaks

"Understanding how a virus enters and infects cells is fundamental.

The alphaviruses the researchers studied, including EEEV, have a history of causing lethal, short-lived outbreaks, but little is known about how viruses attack host cells

infected mosquito

triple E is usually transmitted to humans through the bite of an infected mosquito

The virus has a 30% fatality rate, meaning nearly one-third of confirmed patients will die from the virus, comparable to Ebola virus disease or smallpox

Abraham said there are great benefits to doing this work before a major outbreak

For example, during the SARS outbreak in the early 2000s, previous work on SARS-CoV was critical to strengthening preparedness against SARS-CoV-2

New screening tools and techniques in molecular biology, protein biochemistry, biophysics and structural biology offer unprecedented power to understand viruses better than ever before they become a global threat, Abraham said basic biology

"The time to prepare for these uncertain but potentially catastrophic situations is not when they happen, but long before they happen," Abraham said

gene editing

In the current study, the researchers first used a CRISPR-Cas9 gene-editing screen to identify receptors for the Semliki Forest virus (SFV) on human cells

The researchers found that SFV's receptor is also compatible with EEEV and another related virus called Sindbis, which causes fever and severe joint pain in humans and neurological disease in animals and rodents.

"That's why it's important to study these viruses as families," Abraham said

Identifying the receptors for multiple viruses will lay the groundwork for scientists and doctors to develop tools to prevent, control and treat infections in case one of them breaks out, Abraham said

The validation question is that the receptors are important for causing infection, and the researchers conducted extensive experiments on the decoy protein, a molecular structure that mimics the receptor that can entice a viral drug rather than bind to it designed to infect host cells

The team's experiments showed that preventing the virus from interacting with host cell receptors prevented neuronal infection in humans and mice
.
They also found that the decoy molecules protected the infected mice from rapidly developing deadly type A virus encephalitis
.
The findings suggest that drugs or antibodies could target this pathway when humans are infected with encephalitis A, the researchers said
.
The team of scientists cautioned that they conducted animal studies with Semliki Forest virus rather than EEEV, so further experiments are needed to verify whether the same approach works with different alphaviruses and humans
.

Translating such fundamental insights into clinical tools often takes years
.
Researchers need to make sure it's safe and effective, and need to find the best way to manage the decoy molecules
.
In order to buy as much time in advance as possible to prepare for an emerging virus, it is crucial to build this knowledge base before the next pandemic, Abraham said
.

"All of us -- scientists, policy makers and citizens -- would greatly benefit from learning to think more forward-looking," Abraham said.
" The more
we learn about the basic biology of different virus families, especially It's how they infect and interact with the host, and we're better equipped to deal with whatever comes next
.
"

Journal Reference :

1. Lars E.
   Clark, Sarah A.
   Clark, ChieYu Lin, Jianying Liu, Adrian Coscia, Katherine G.
   Nabel, Pan Yang, Dylan V.
   Neel, Hyo Lee, Vesna Brusic, Iryna Stryapunina, Kenneth S.
   Plante, Asim A.
   Ahmed , Flaminia Catteruccia, Tracy L.
   Young-Pearse, Isaac M.
   Chiu, Paula Montero Llopis, Scott C.
   Weaver, Jonathan Abraham.
   VLDLR and ApoER2 are receptors for multiple alphaviruses .
   Nature , 2021; DOI: 10.
   1038/s41586-021-04326 -0