Study reveals how tick-borne encephalitis virus enters cells

September 24, 2025 (BRONX, NY)—The protein on human cells that tick-borne encephalitis virus (TBEV) uses for infection has now been identified—a major step toward understanding how TBEV causes neurological disease and for developing antiviral drugs. The study, co-led by scientists at Albert Einstein College of Medicine, Karolinska Institutet, and the United States Army Medical Research Institute of Infectious Diseases (USAMRIID) published today in the journal Nature.

TBEV is one of many mosquito- and tick-borne flaviviruses responsible for serious diseases, which also include dengue virus, yellow fever virus, Zika virus, and Japanese encephalitis virus. “But until now, scientists have been unable to identify essential host-cell protein receptors for any flavivirus,” said study co-leader Kartik Chandran, Ph.D., professor of microbiology & immunology, the Gertrude and David Feinson Chair in Medicine, and the Harold and the Muriel Block Faculty Scholar in Virology at Einstein. “By conclusively demonstrating that TBEV requires a critical protein receptor to infect human cells, we open the field to discovering receptors for other flaviviruses and devising therapies for the devastating infections they cause.”

The paper’s other corresponding authors are Eva Mittler, Ph.D., at Einstein; Andrew Herbert, Ph.D., at USAMRIID, Fort Detrick, MD; and Sara Gredmark-Russ, M.D., Ph.D., at Karolinska Institutet, Sweden.

Tackling a Growing Threat
TBEV is carried by ticks that usually transmit the disease to humans through bites. The virus can infect the brain and spinal cord, causing severe and sometimes life-threatening disease. TBEV is endemic throughout Northern, Central and Eastern Europe, and Central and East Asia, where it causes more than 10,000 clinical cases a year, some of them fatal.

“The number of cases caused by TBEV is likely to grow as the geographic range of the tick that spreads the infection continues to move into new areas,” said Dr. Mittler, research assistant professor of microbiology & immunology at Einstein. “Several TBEV vaccines have been approved, but access to them is limited, especially in low-and middle-income countries in the endemic zone, and there are no specific treatments for people already infected with TBEV.”

In seeking the receptor that TBEV “unlocks” to gain entry to human cells, the research team suspected that a cell protein was being targeted. Using a human cell line, they amassed a “library” of thousands of cell variants in which a different gene had been deleted; the variants were then exposed to TBEV. Only cell types lacking a gene necessary for TBEV infection should survive virus exposure.

Unmasking the Culprit 
As expected, this “Survivor-like” competition implicated a number of genes that might be important for viral infection, most of which had been found previously for other flaviviruses. “What really stood out in our screen was the gene for LRP8, a low-density lipoprotein receptor located on the surface of cells,” said Dr. Gredmark-Russ, associate professor of infectious diseases at Karolinska Institutet. LRP8 is highly expressed in the brain and at the blood-brain barrier and plays special roles in neurological development and function. The team showed that LRP8 is specifically recognized by TBEV’s envelope protein E, known to play crucial roles in host cell entry, immune evasion, and viral spread. “LRP8 appeared to be the long-sought cell-surface protein to which TBEV must bind in order to enter and infect human cells, including key cell types in the brain such as neurons,” said Dr. Chandran.

In a key follow-up experiment, members of the team at USAMRIID led by Dr. Herbert, branch chief of viral immunology, determined that LRP8 is important for TBEV infection in living organisms—mice, in this case. They treated mice with a “decoy receptor” that prevents TBEV from binding to LRP8 on cells. They then exposed the mice to a highly virulent strain of TBEV. Nineteen of the 20 animals treated with the decoy receptor did not develop any clinical signs of infection. By contrast, all untreated mice rapidly developed severe disease and succumbed to infection. “It was really exciting to see that LRP8 is crucial for TBEV to efficiently infect the brain,” Dr. Herbert said.

“We need to perform further laboratory and animal studies to understand exactly how LRP8 allows TBEV to infect people and cause neurological disease,” Dr. Gredmark-Russ said. Dr. Chandran added that “it would also be fascinating to learn whether the virus uses similar proteins to colonize ticks, which are part of the viruses’ natural life cycle and transmit the virus to people.”

“More research is needed, but this is a promising start toward developing new measures for preventing and treating flavivirus infections,” added Dr. Mittler.

The study is titled, “LRP8 is a receptor for tick-borne encephalitis virus.” The co-first authors are Dr. Mittler;  Alexandra L. Tse, M.S., and an M.D./Ph.D. student at Einstein; Pham-Tue-Hung Tran, Ph.D. (Karolinska Institutet); and Catalina Florez, Ph.D. (USAMRIID). Additional Einstein authors include Javier Janer, Ezgi Kasikci, Ph.D., Vasantha Kumar MV, Ph.D., Caroline K. Martin, Ph.D., Megan M. Slough, Ph.D., Denise Haslwanter, Ph.D., Jacob Berrigan, Margaret Kielian, Ph.D., and Evripidis Gavathiotis, Ph.D. Other authors include Renata Varnaite, PhD., Wanda Christ, Ph.D., Mansoureh Shahsavani, Ph.D., and Anna Falk, Ph.D. (all at Karolinska Institutet), Jonas Klingström., Ph.D. (at Linköping University; Linköping. Sweden), Sara Khanal, Eric R. Wilkinson, Michaela Loomis, Erik Cazares, Ph.D., Russell R. Bakken, Xiankun Zeng, Ph.D., and Jo Lynne Raymond, D.V.M. (all at USAMRIID; Fort Detrick, MD), Rischa Maya Oktavia, Giovanna Barba-Spaeth, Ph.D., and Felix A. Rey, Ph.D. (all at Institut Pasteur; Paris, France), Ebba Rosendal and Anna K. Överby, Ph.D. (both at Umeå University; Umeå, Sweden), Julianna Han, Ph.D. at University of Chicago; Chicago, IL, and Balaji Manicassamy, Ph.D. at University of Iowa; Iowa City, IA.

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About Albert Einstein College of Medicine 
Albert Einstein College of Medicine is one of the nation’s premier centers for research, medical education and clinical investigation. During the 2024-25 academic year, Einstein is home to 712 M.D. students, 226 Ph.D. students, 112 students in the combined M.D./Ph.D. program, and approximately 250 postdoctoral research fellows. The College of Medicine has more than 2,000 full-time faculty members located on the main campus and at its clinical affiliates. In 2024, Einstein received more than $192 million in awards from the National Institutes of Health. This includes the funding of major research centers at Einstein in cancer, aging, intellectual development disorders, diabetes, clinical and translational research, liver disease, and AIDS. Other areas where the College of Medicine is concentrating its efforts include developmental brain research, neuroscience, cardiac disease, and initiatives to reduce and eliminate ethnic and racial health disparities. Its partnership with Montefiore, the University Hospital and academic medical center for Einstein, advances clinical and translational research to accelerate the pace at which new discoveries become the treatments and therapies that benefit patients. For more information, please visit einsteinmed.edu, follow us on Twitter, Facebook, Instagram, LinkedIn, and view us on YouTube.