Research identifies mobile receptors for alphaviruses shared by mosquitoes, people and animals

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A new study led by Harvard Medical School researchers has identified a set of cellular receptors for at least three related alphaviruses shared by mosquitoes, humans and animals that harbor the virus.

The researchers went a step further and tested a “bait” molecule that successfully prevented infection and slowed disease progression in a series of experiments in cells and animal models, an important first step in developing preventive and curative drugs against these highly pathogenic ones Viruses with Pandemic Potential.

The results were published in Nature on December 20.

Understanding the basic biology of a virus’ life cycle is critical to finding a way to prevent disease, and building such basic knowledge before an outbreak is essential to preparing for future outbreaks, said the study’s lead author Jonathan Abraham, an assistant professor of microbiology at the Blavatnik Institute at HMS and an infectious disease specialist at Brigham and Women’s Hospital.

“Understanding how a virus enters a cell and infects it is as basic as it gets,” he said. “Viral entry into human or other mammalian cells marks the onset of infection and eventual disease and is a great starting point to search for potential preventive strategies and curative drugs.”

The alphaviruses studied by the researchers, including EEEV, have caused deadly if short-lived outbreaks in the past, but little is known about how the virus attacks host cells. Few other receptors associated with alphavirus infection have been identified. This knowledge gap is one of the reasons for the lack of targeted treatments for these deadly viruses, Abraham said.

Eastern equine encephalitis (triple E) typically spreads to humans through the bite of an infected mosquito. The most recent eruption of Triple E was in New England in 2019. The Triple-E outbreak hospitalized all 32 known cases and killed 12 of those infected, according to a report by the US Centers for Disease Control and Prevention on the 2019 Triple-E outbreak.

The virus has a 30 percent mortality rate — meaning it kills nearly a third of people diagnosed with the disease — comparable to Ebola virus disease or smallpox. Nearly half of those who survive will experience long-term neurological complications from the disease, according to the CDC. Major outbreaks occurred in the 1930s and 1950s, but data collection and diagnosis have changed so much since then that it’s difficult to compare the magnitude of outbreaks, the CDC report noted.

There are major benefits to doing this work before the onset of major outbreaks, said Abraham, who has worked on identifying receptors that viruses use as pathways to enter cells and cause disease and on developing antibody treatments to prevent one SARS-CoV-2 infection and COVID-19.

For example, previous work on SARS-CoV during the SARS outbreak in the early 2000s was critical to improving preparedness against SARS-CoV-2. The availability of SARS-CoV-2 genome sequences within days after the novel virus was first reported was critical to the rapid development of vaccines and antibody treatments for COVID-19, as the closely related viruses that cause COVID-19 and SARS attack both human hosts, using the same receptor on human cells to gain entry and cause disease.

New screening tools and techniques in molecular biology, protein biochemistry, biophysics and structural biology offer an unprecedented opportunity to learn more than ever about the basic biology of viruses before they become global threats, Abraham said.

“The time to prepare for these uncertain but potentially catastrophic scenarios is not when they happen, but well before they do,” Abraham said.

For the current study, researchers first used a CRISPR-Cas9 gene-editing screen to identify a Semliki Forest Virus (SFV) receptor on human cells. SFV is an alphavirus that can cause severe neurological disease and death in rodents and other animals.

The receptors the researchers found for SFV were also compatible with EEEV and another related virus called Sindbis, which can cause fever and severe joint pain in humans and cause neurological disorders in animals and rodents

Therefore, it is important to study these viruses as families. In the end, you can study a virus like SFV and discover something really exciting about the biology of related viruses that has the potential to open up new ways of treating new categories of viruses that are capable of causing serious diseases and outbreaks in humans .”

Jonathan Abraham, senior study author, assistant professor, microbiology, Blavatnik Institute, HMS and infectious disease specialist, Brigham and Women’s Hospital.

Identifying a receptor for several viruses would give scientists and doctors a jump start on developing tools to prevent, control and treat infections should one of the viruses break out, Abraham said.

To verify that the receptors in question are important to the infection, the researchers conducted experiments using a bait protein, a molecule with a structure that mimics the receptor and can trick the virus into attaching to the drug rather than the host cell aims to infect. The molecule deactivates the virus and prevents it from entering the host cell, preventing infection.

The team’s experiments showed that blocking the virus’ interaction with the host cell receptor prevented infection of human and mouse neurons. They also found that the decoy molecule protected infected mice from developing rapidly fatal alphaviral encephalitis – a finding the researchers say this pathway could be targeted by drugs or antibodies to treat human alphaviral encephalitis. when infections occur. The researchers note that they conducted their animal studies with Semliki Forest virus and not EEEV, so more experiments would be needed to confirm that the same approach could work for different alphaviruses and in humans.

Turning a fundamental discovery like this into a clinical tool usually takes years. Researchers need to make sure it’s safe and effective, and figure out the best way to administer the decoy molecules. To gain that much time in advance to prepare for emerging viruses, building that knowledge base ahead of the next pandemic is crucial, Abraham said.

Source:

Magazine reference:

Clark, LE, et al. (2022) VLDLR and ApoER2 are receptors for several alphaviruses. Nature. doi.org/10.1038/s41586-021-04326-0

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