"Flaviviruses exact an enormous toll in terms of illness and death worldwide," notes NIAID Director Anthony S. Fauci, M.D. "Because this is a relatively new field of study, everything we learn about how these viruses operate is significant. This elegant work opens an array of new questions and research opportunities to pursue as we strive to better understand this family of viruses and develop countermeasures against them."
Mosquito-borne flaviviruses include West Nile virus, yellow fever virus, dengue virus and Japanese encephalitis virus; the less-familiar tick-borne flaviviruses are just as serious, causing tick-borne encephalitis or hemorrhagic fevers. Currently, a Japanese encephalitis outbreak is raging in India and Nepal and has killed more than 1,000 people. In Europe and Southeast Asia, tick-borne encephalitis typically results in more than 10,000 patient visits to hospitals annually and has a fatality rate of up to 25 percent in some regions. Viruses that cause encephalitis lead to inflammation of the brain. Hemorrhagic fevers are viral infections that cause capillaries to burst, leading to unusual bleeding on or under the skin or in various organs.
The study released this week online in the Journal of Virology describes how a single virus protein--NS5--from the tick-borne Langat flavivirus counteracts the natural ability of interferon to combat the virus. Langat virus was originally isolated in the 1950s in Malaysia and Thailand. Langat virus can infect people following a tick bite, but there are no cases of natural disease recorded. In the 1970s Langat was briefly used as a live vaccine against more virulent tick-borne encephalitis viruses in Russia but caused encephalitis complications in about 1 of every 10,000 people.
Interferon, the body's first defense against many viruses, triggers a cascade of immune defenses. According to researchers at NIAID's Rocky Mountain Laboratories (RML) in Hamilton, MT, NS5 blocks the body's attempt to signal for immune defenses, preventing the immune system from both stopping the spread of virus and helping the body recover from infection.
Interferon is so critical for recovery from these infections that it is being tested in clinical trials to treat infection with various flaviviruses. But the treatment appears to fail in about half of cases. Dengue virus, West Nile virus and yellow fever virus have a protein called NS4B that prevents interferon from functioning properly. It was thought that the tick-borne flaviviruses would use the same protein, so the NS5 finding was unexpected.
The RML group, directed by Marshall Bloom, M.D., chose Langat virus because it is spread by ticks--a trademark of RML expertise--and because it possesses the same survival mechanisms as the more serious tick-borne encephalitis, Omsk hemorrhagic fever (found in western Siberia) and the closely related Kyasanur forest disease (found in western India).
"These diseases are spread by the same tick that carries Lyme disease in the U.S.," says Dr. Bloom. "So, the fact that West Nile virus first appeared or emerged in the U.S. in 1999 should warn us about the potential for tick-borne flaviviruses to emerge on other continents." In preparation for such a development, Dr. Fauci notes that two other NIAID laboratories have similar flavivirus studies under way, and the three groups are building on the discoveries of each other.
Dr. Bloom says that all flaviviruses have a similar genomic structure, and many scientists thought they would use the same survival mechanism and respond to the same vaccines and therapies, but the RML work shows otherwise.
"NS5 prevents interferon from doing its sentry job and allows the virus to take over cells," says Dr. Bloom. "This is the first definitive study that dissects where the failure occurs in the signaling pathway, and then identifies some of the interacting partners in the cell and virus." Prior to this work, Dr. Bloom says, scientists knew only that NS5 helped tick-borne flaviviruses replicate.
RML's Sonja Best, Ph.D., who spearheaded the Langat virus work, says the group will continue to study tick-borne flaviviruses by examining the role and location of NS5 in Powassan virus. Powassan virus, found in North America, Russia, China and Southeast Asia, rarely infects people but is potentially fatal. If the research group can track the movement of NS5 in Powassan-infected cells and learn how it interacts with other proteins to block immune defenses, "that would provide a target for therapeutics to counteract tick-borne flaviviruses," says Dr. Best.
NIAID is a component of the National Institutes of Health, an agency of the U.S. Department of Health and Human Services. NIAID supports basic and applied research to prevent, diagnose and treat infectious diseases such as HIV/AIDS and other sexually transmitted infections, influenza, tuberculosis, malaria and illness from potential agents of bioterrorism. NIAID also supports research on transplantation and immune-related illnesses, including autoimmune disorders, asthma and allergies.
Reference: S. Best et al. Inhibition of interferon-stimulated JAK-STAT signaling by a tick-borne Flavivirus and identification of NS5 as an interferon antagonist. Journal of Virology. DOI: 10.1128/JVI.79.20
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