Researchers have Discovered a Set of Virus-Hosting Cellular Receptors

A new study led by Harvard Medical School researchers has discovered a set of cellular receptors for at least three related alphaviruses that are found in mosquitos, humans, and animals that carry the virus.

In a series of experiments in cells and animal models, the researchers tested a “decoy” molecule that successfully prevented infection and slowed disease progression, a critical first step toward developing preventive and curative medicines against these highly pathogenic viruses with pandemic potential.

The results were published on December 20 in Nature.

According to study senior author Jonathan Abraham, an infectious disease specialist at Brigham and Women’s Hospital and assistant professor of microbiology in the Blavatnik Institute at HMS, “understanding the basic biology of a virus’s life cycle is crucial for finding a way to prevent an illness,” and “building such foundational knowledge before an outbreak is essential for preparing for future outbreaks.”

“Understanding how a virus enters and infects a cell is as basic as it gets,” he said. “Viral entry into human or other mammalian cells marks the beginning of the infection and eventually disease, and is a great place to begin looking for potential preventive strategies and curative medications.”

The alphaviruses researched by the researchers, including EEEV, have a history of creating lethal, albeit brief, epidemics, but little is known about how they target host cells. Only a few additional receptors linked to alphavirus infection have been discovered. According to Abraham, one of the reasons for the lack of focused therapeutics for these fatal viruses is a knowledge gap.

Understanding how a virus enters and infects a cell is as basic as it gets. Viral entry into human or other mammalian cells marks the beginning of the infection and eventually disease, and is a great place to begin looking for potential preventive strategies and curative medications.

Jonathan Abraham

Infected mosquitoes

Eastern equine encephalitis (triple E) is usually transmitted to humans by a mosquito bite. The most recent triple E epidemic occurred in New England in 2019. According to a US Centers for Disease Control and Prevention report on the 2019 triple E outbreak, the outbreak hospitalized all 32 confirmed patients and killed 12 of those afflicted.

The virus has a 30 percent mortality rate, which means it kills roughly one-third of individuals infected, similar to the Ebola virus or smallpox. According to the CDC, about half of those who survive to get long-term neurologic issues as a result of the disease.

Larger outbreaks occurred in the 1930s and 1950s, but data collection and diagnosis have changed so much since then that comparing the severity of the outbreaks is impossible, according to the CDC analysis.

According to Abraham, who has worked on identifying receptors that viruses use as pathways for gaining entry into cells and causing disease, as well as developing antibody treatments to prevent SARS-CoV-2 infection and COVID-19, doing this work before the onset of major outbreaks has significant benefits.

Prior work on SARS-CoV during the early 2000s SARS outbreak, for example, was critical to enhancing preparation against SARS-CoV-2. Because the closely related viruses that cause COVID-19 and SARS both attack human hosts by using the same receptor on human cells to gain entry and cause disease, the availability of SARS-CoV-2 genome sequences within days of the novel virus’s initial reporting was critical to the rapid development of vaccines and antibody treatments for COVID-19.

New screening tools and techniques in molecular biology, protein biochemistry, biophysics, and structural biology provide researchers more power than ever before to understand more about the underlying biology of viruses before they become global hazards, according to Abraham.

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

Gene-editing screen

The researchers employed a CRISPR-Cas9 gene-editing screen to find a Semliki Forest virus (SFV) receptor on human cells for the current study. In rodents and other animals, SFV is an alphavirus that can cause serious brain illness and death.

The SFV receptors discovered by the researchers were also compatible with EEEV and Sindbis, a related virus that causes fever and severe joint pain in people and neurological illness in animals and rodents.

“That’s why it’s important to study these viruses as families,” Abraham said. “You can end up studying a virus-like SFV and discover something really exciting about the biology of related viruses that has the potential to unlock novel ways to treat new categories of viruses that are capable of causing serious disease and outbreaks in humans.”

Identifying a receptor for several viruses would offer scientists and doctors a head start on developing ways to prevent, control, and treat diseases if one of the viruses were to spread, Abraham explained.

The researchers used a decoy protein, a molecule with a structure that mimics the receptor and can deceive the virus into adhering to the drug instead of the host cell it wants to infect, to validate that the receptors in issue were critical in inducing infection.

The chemical effectively inhibits the virus and prevents it from infecting the host cell. The researchers found that preventing the virus from connecting with the host cell receptor prevented infection of human and mouse neurons in their trials.

They also discovered that the decoy molecule protected infected mice from developing rapidly deadly alphavirus encephalitis, a discovery that implies this route may be targeted by medications or antibodies to treat alphavirus encephalitis in humans if infections do occur, according to the researchers.

The researchers point out that they used Semliki Forest virus in their animal trials rather than EEEV, so more research is needed to see if the same strategy will work with other alphaviruses and in humans.

It takes years to turn a simple observation like this into a clinical tool. Researchers must ensure that it is both safe and effective, as well as determine the optimal method for administering the decoy molecules.

It’s vital to create this knowledge foundation before the next pandemic to buy as much time as possible to prepare for emerging viruses, Abraham added.

“All of us scientists, policymakers, and citizens would benefit greatly from learning to be more forward thinking,” Abraham said. “The more we know about the basic biology of different families of viruses, especially how they infect and interact with their hosts, the better prepared we will be to face whatever comes next.”

Co-authors included Lars Clark, Sarah Clark, ChieYu Lin, Adrian Coscia, Katherine Nabel, Dylan Neel, Isaac Chiu, Paula Montero Llopis, Tracy Young-Pearse, Pan Yang, and Vesna Brusic at Harvard Medical School; Asim Ahmed at Boston Children’s Hospital; Jianying Liu and Kenneth Plante, and Scott Weaver at the University of Texas Medical Branch; and Iryna Stryapunina and Flaminia Catteruccia at the Harvard T.H. Chan School of Public Health.

The US Department of Health and Human Services, the National Institutes of Health, the Burroughs Wellcome Fund, the William Randolph Hearst Foundation, the Brigham and Women’s Hospital Harvard Milton Fund, the Vallee Scholar Award, and the Howard Hughes Medical Institute all contributed to this research.

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