Researchers Identify Viral Entry Routes and Develop Decoy Molecules to Block Deadly Yellow Fever and Tick-Borne Encephalitis Viruses

Researchers at Washington University School of Medicine in St. Louis have made a breakthrough discovery in understanding how two deadly viruses invade human cells, identifying specific cellular entry routes and developing innovative decoy molecules that successfully block these infections. The findings, published in two separate studies in Nature and PNAS, represent the first comprehensive understanding of viral entry mechanisms that have puzzled scientists for over a century.

Breakthrough in Viral Entry Mechanisms

The research team, led by Michael S. Diamond, MD, PhD, used genetic techniques including CRISPR gene editing technology to identify a family of cell-surface proteins called low-density lipoprotein receptors (LDLR) as the primary routes these viruses use to enter cells. This discovery addresses a fundamental gap in scientific understanding that has persisted despite decades of research.

"There are no treatments for these viral infections, so there is an urgent need for new strategies to prevent and treat these infections, which continue to cause severe disease and death in far too many cases," said Diamond, senior author of both studies and the WashU Medicine Herbert S. Gasser Professor of Medicine.

The researchers focused on LDLR proteins based on their previous work identifying these receptors as important entry points for other viruses, including alphaviruses such as Venezuelan equine encephalitis virus. Their investigation revealed that yellow fever virus latches onto LDLR receptors LRP1 (搜索)搜索该靶点, LRP4 (搜索)搜索该靶点 and VLDLR (搜索)搜索该靶点, while tick-borne encephalitis viruses enter cells via a different family member, LRP8 (搜索)搜索该靶点.

Organ-Specific Viral Targeting Explained

The specific receptors identified help explain why these viruses cause different types of organ damage. High amounts of LRP1 (搜索)搜索该靶点 are found on liver cell surfaces, correlating with yellow fever virus's ability to cause severe liver disease. Similarly, LRP8 (搜索)搜索该靶点 is found primarily on nervous system cell surfaces, explaining the severe neurological symptoms characteristic of tick-borne encephalitis virus infections.

The researchers validated their findings by genetically eliminating these receptor proteins from cell surfaces, which completely blocked viral infections. Conversely, adding abnormally high numbers of these receptors to cells allowed increased viral entry, confirming the receptors' critical role in infection.

Innovative Decoy Strategy Shows Promise

The team developed "decoy" molecules that include antibody fragments attached to the viral entry receptors. These decoys are not embedded in cells but instead float freely, tricking viruses into binding to them rather than actual cells. This strategy successfully prevented infection in both human and mouse cells in laboratory studies.

In animal testing, the decoy molecules protected immunodeficient mice from typically lethal doses of yellow fever virus, compared with mice receiving placebo decoys. The receptor decoys also prevented liver cell damage in mice engrafted with human liver cells, demonstrating their protective potential across different tissue types.

Addressing Critical Public Health Needs

Yellow fever virus, spread by mosquitoes, is common in parts of Africa and South America. According to the World Health Organization, approximately 15% of infections are severe, causing high fever, liver failure, internal bleeding and toxic shock. About half of cases that come to clinical attention—numbering in the tens of thousands annually—end in multi-organ failure and death.

Current yellow fever vaccination relies on a live virus vaccine developed in 1937, which cannot be safely administered to people with weakened immune systems, including infants and older adults. Tick-borne encephalitis virus, spread by several tick species across Europe, Russia and Northern and Eastern Asia, causes brain and spinal cord inflammation leading to neurological disease and death. An inactivated vaccine exists for only one subtype and is primarily recommended for high-risk travelers.

Strategic Advantages of the Approach

According to the researchers, this antiviral strategy offers significant advantages because the decoys are based on human proteins that won't evolve, rather than viral proteins that constantly adapt to evade therapies. Diamond noted that if viruses mutate to evade the decoys, they would simultaneously reduce their ability to bind human proteins, potentially making them less infectious.

"Our studies showing how these viruses get into cells creates opportunities to disrupt those routes, stopping viral infections from jumping animal species—both wild and domesticated—and spreading through populations of people," Diamond explained.

Co-author Daved Fremont, PhD, a professor of pathology and immunology, biochemistry and molecular biophysics, and molecular microbiology at WashU Medicine, emphasized the broader implications: "Our new studies are a step toward the development of a new generation of vaccines and antiviral strategies for active infections."

Implications for Broader Virus Families

These discoveries have particular relevance as climate change expands the geographic ranges of virus-carrying vectors, increasing public health threats from virus families that include Zika, dengue, West Nile and Japanese encephalitis viruses. The research establishes a foundation for developing new prevention and treatment strategies for these expanding viral threats.

The findings represent a significant advance in understanding viral pathogenesis and offer a promising new therapeutic approach that could be adapted for multiple related viruses, potentially addressing a critical gap in antiviral treatment options.