Researchers have identified the protein on human cells that tick-borne encephalitis virus (TBEV) uses to infect its host. This discovery marks a significant advance in understanding how TBEV causes neurological disease and could inform future antiviral drug development. The study, published in Nature, was led by scientists from Albert Einstein College of Medicine, Karolinska Institutet, and the United States Army Medical Research Institute of Infectious Diseases (USAMRIID).
TBEV is among several mosquito- and tick-borne flaviviruses that cause serious diseases, including dengue, yellow fever, Zika, and Japanese encephalitis. “But until now, scientists have been unable to identify essential host-cell protein receptors for any flavivirus,” said Kartik Chandran, Ph.D., professor 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.”
Other corresponding authors of the paper include Eva Mittler, Ph.D., at Einstein; Andrew Herbert, Ph.D., at USAMRIID; and Sara Gredmark-Russ, M.D., Ph.D., at Karolinska Institutet.
TBEV is spread through tick bites and can affect the brain and spinal cord with severe outcomes. It is endemic in Northern, Central and Eastern Europe as well as Central and East Asia. Each year it causes more than 10,000 clinical cases globally.
“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. “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.”
To identify which cell protein allows TBEV entry into human cells, researchers used a library of thousands of human cell variants each lacking a different gene. Only those without genes needed for infection survived exposure to TBEV.
The research pointed strongly toward LRP8—a low-density lipoprotein receptor present on cell surfaces—as crucial for infection. “What really stood out in our screen was the gene for LRP8,” said Dr. Gredmark-Russ. The team found that LRP8 is highly expressed in brain tissue and plays roles in neurological function. They demonstrated that TBEV’s envelope protein E specifically binds LRP8 during infection. “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.
A follow-up experiment at USAMRIID showed that treating mice with a decoy receptor blocking LRP8 protected nearly all animals from developing symptoms after exposure to a virulent strain of TBEV; untreated mice developed severe disease rapidly. “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 stated. Dr. Chandran added: “it would also be fascinating to learn whether the virus uses similar proteins to colonize ticks…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’s co-first authors are Dr. Mittler; Alexandra L. Tse (Einstein); Pham-Tue-Hung Tran (Karolinska Institutet); Catalina Florez (USAMRIID). Additional contributors come from multiple institutions across Sweden, France, and the United States.
