In a groundbreaking scientific advancement published in the prestigious journal Nature on September 24, 2025, an international team of researchers co-led by scientists from Albert Einstein College of Medicine, Karolinska Institutet, and the United States Army Medical Research Institute of Infectious Diseases (USAMRIID) has identified the elusive cellular receptor that enables tick-borne encephalitis virus (TBEV) to infect human cells. This discovery represents a pivotal step in unraveling the molecular mechanisms underlying TBEV infection, a virus responsible for severe neurological diseases, and opens new avenues for antiviral drug development.
TBEV is a member of the flavivirus genus, a category that includes other prominent viruses such as dengue, yellow fever, Zika, and Japanese encephalitis viruses. These mosquito- and tick-borne pathogens are notorious for causing widespread morbidity and mortality globally. Despite extensive research, the precise host-cell proteins facilitating the entry of flaviviruses into human cells had remained unidentified until now. This study definitively demonstrates that TBEV requires interaction with a specific receptor on human cells to initiate infection, a discovery that could revolutionize efforts to combat flavivirus-related diseases.
Tick-borne encephalitis virus is predominantly transmitted via ticks, which bite humans and transfer the virus, leading to infections that can invade the central nervous system—including the brain and spinal cord—resulting in potentially fatal neurological symptoms. The incidence of TBEV infections, currently exceeding 10,000 clinical cases annually, is anticipated to rise as climate changes and expanding tick habitats enable the vector to colonize new geographic areas, spreading the disease further throughout Northern, Central, and Eastern Europe as well as Central and East Asia.
In their search for the viral receptor, the scientists utilized an expansive screening approach involving a human cell line engineered to contain thousands of genetic variants, each lacking a different gene. This loss-of-function library was exposed to TBEV under controlled experimental conditions, with surviving cells suspected of missing genes essential for viral infection. From this competitive selection, the gene encoding the receptor protein LRP8 distinctly emerged as a critical factor required for TBEV entry into human cells.
LRP8, or low-density lipoprotein receptor-related protein 8, is localized on the surface of various human cells, with particularly high expression in the brain and at the blood-brain barrier. This receptor is classically known for its roles in neurological development and neuronal signaling pathways. The study revealed that TBEV directly engages LRP8 via its envelope protein E, a glycoprotein instrumental in viral attachment, immune evasion, and propagation within the host. This interaction underpins TBEV’s ability to specifically target and infect neuronal cells, key mediators of neuropathology in TBEV infections.
Further experimental validation by researchers at USAMRIID demonstrated the in vivo relevance of LRP8 by deploying a “decoy receptor” strategy. This therapeutic approach involved administering soluble forms of the LRP8 receptor that bind TBEV in circulation, thereby preventing the virus from engaging cell surface LRP8 and blocking infection. Remarkably, the vast majority of mice treated with the decoy receptor remained free of clinical signs after exposure to a highly virulent TBEV strain, whereas untreated controls rapidly developed severe disease and succumbed. These findings underscore LRP8’s indispensable role in facilitating TBEV neuroinvasion.
Despite these promising results, the scientists emphasize that further research is essential to delineate the precise molecular mechanisms by which LRP8 mediates viral entry and subsequent neurological damage. They are particularly interested in uncovering whether TBEV exploits similar receptor pathways within ticks, which serve as natural reservoirs and vectors, completing the virus’s life cycle. Such insights could be critical for developing integrated strategies to prevent virus transmission.
Given the limited availability of TBEV vaccines, which are largely inaccessible in low- and middle-income regions within endemic zones, and the current absence of targeted antiviral therapies, this receptor discovery carries substantial clinical implications. It opens prospects for novel preventive and therapeutic interventions aimed at disrupting virus-receptor interactions, potentially mitigating the burden of tick-borne encephalitis and related flavivirus infections worldwide.
This landmark study was orchestrated by a coalition of leading scientists in virology, immunology, and infectious diseases. Among the principal investigators were Kartik Chandran, Ph.D., Eva Mittler, Ph.D., Andrew Herbert, Ph.D., and Sara Gredmark-Russ, M.D., Ph.D., whose combined expertise facilitated the comprehensive exploration of TBEV’s host-pathogen interactions. The collaborative nature of this research, spanning several continents and institutions, exemplifies the global effort necessary to confront emerging infectious diseases effectively.
The study also benefits from state-of-the-art methodologies, including genomic knockout libraries, protein-receptor binding assays, and in vivo animal models, underscoring the importance of multidisciplinary approaches in modern infectious disease research. Mapping the virus-host interface at the molecular level facilitates rapid translation of fundamental findings into applied clinical strategies.
By illuminating the critical role of LRP8 as a gateway for TBEV infection, this research signifies a paradigm shift in flavivirus biology, challenging earlier assumptions that cellular entry mechanisms were unknown. The elucidation of this receptor not only enhances our understanding of TBEV pathogenesis but also serves as a template for investigating receptor usage by other flaviviruses, which continue to impose significant global health challenges through epidemics and endemic disease burdens.
In summary, the identification of LRP8 as the receptor essential for TBEV infection constitutes a major advance in virus-host biology, with profound implications for developing antiviral drugs, designing vaccines, and improving public health responses to tick-borne encephalitis. Amidst a landscape of climate change and expanding vector habitats, such scientific breakthroughs are urgently needed to anticipate and contain emerging viral threats to human populations.
Subject of Research: Cells
Article Title: “LRP8 is a receptor for tick-borne encephalitis virus.”
News Publication Date: 24-Sep-2025
Image Credits: Albert Einstein College of Medicine
Keywords: Cell biology, Virology, Tick-borne encephalitis virus, Flavivirus, LRP8 receptor, Neurological disease, Virus-host interactions, Antiviral therapy, Viral entry mechanisms
