Researchers from the National Institute of Allergy and InfectiousDiseases (NIAID), part of the National Institutes of Health, have madethe surprising discovery that flaviviruses, which cause such seriousdiseases as West Nile fever, yellow fever and forms of encephalitis,evade immune system defenses in different ways depending on whetherthey are transmitted by mosquitoes or ticks. This finding could lead tonew approaches to developing vaccines and treatments against theseillnesses.
"Flaviviruses exact an enormous toll in terms of illness and deathworldwide," notes NIAID Director Anthony S. Fauci, M.D. "Because thisis a relatively new field of study, everything we learn about how theseviruses operate is significant. This elegant work opens an array of newquestions and research opportunities to pursue as we strive to betterunderstand this family of viruses and develop countermeasures againstthem."
Mosquito-borne flaviviruses include West Nile virus, yellowfever virus, dengue virus and Japanese encephalitis virus; theless-familiar tick-borne flaviviruses are just as serious, causingtick-borne encephalitis or hemorrhagic fevers. Currently, a Japaneseencephalitis outbreak is raging in India and Nepal and has killed morethan 1,000 people. In Europe and Southeast Asia, tick-borneencephalitis typically results in more than 10,000 patient visits tohospitals annually and has a fatality rate of up to 25 percent in someregions. Viruses that cause encephalitis lead to inflammation of thebrain. Hemorrhagic fevers are viral infections that cause capillariesto burst, leading to unusual bleeding on or under the skin or invarious organs.
The study released this week online in the Journal of Virologydescribes how a single virus protein--NS5--from the tick-borne Langatflavivirus counteracts the natural ability of interferon to combat thevirus. Langat virus was originally isolated in the 1950s in Malaysiaand Thailand. Langat virus can infect people following a tick bite, butthere are no cases of natural disease recorded. In the 1970s Langat wasbriefly used as a live vaccine against more virulent tick-borneencephalitis viruses in Russia but caused encephalitis complications inabout 1 of every 10,000 people.
Interferon, the body's first defense against many viruses,triggers a cascade of immune defenses. According to researchers atNIAID's Rocky Mountain Laboratories (RML) in Hamilton, MT, NS5 blocksthe body's attempt to signal for immune defenses, preventing the immunesystem from both stopping the spread of virus and helping the bodyrecover from infection.
Interferon is so critical for recovery from these infectionsthat it is being tested in clinical trials to treat infection withvarious flaviviruses. But the treatment appears to fail in about halfof cases. Dengue virus, West Nile virus and yellow fever virus have aprotein called NS4B that prevents interferon from functioning properly.It was thought that the tick-borne flaviviruses would use the sameprotein, so the NS5 finding was unexpected.
The RML group, directed by Marshall Bloom, M.D., chose Langatvirus because it is spread by ticks--a trademark of RML expertise--andbecause it possesses the same survival mechanisms as the more serioustick-borne encephalitis, Omsk hemorrhagic fever (found in westernSiberia) and the closely related Kyasanur forest disease (found inwestern India).
"These diseases are spread by the same tick that carries Lymedisease in the U.S.," says Dr. Bloom. "So, the fact that West Nilevirus first appeared or emerged in the U.S. in 1999 should warn usabout the potential for tick-borne flaviviruses to emerge on othercontinents." In preparation for such a development, Dr. Fauci notesthat two other NIAID laboratories have similar flavivirus studies underway, and the three groups are building on the discoveries of eachother.
Dr. Bloom says that all flaviviruses have a similar genomicstructure, and many scientists thought they would use the same survivalmechanism and respond to the same vaccines and therapies, but the RMLwork shows otherwise.
"NS5 prevents interferon from doing its sentry job and allowsthe virus to take over cells," says Dr. Bloom. "This is the firstdefinitive study that dissects where the failure occurs in thesignaling pathway, and then identifies some of the interacting partnersin the cell and virus." Prior to this work, Dr. Bloom says, scientistsknew 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 byexamining the role and location of NS5 in Powassan virus. Powassanvirus, found in North America, Russia, China and Southeast Asia, rarelyinfects people but is potentially fatal. If the research group cantrack the movement of NS5 in Powassan-infected cells and learn how itinteracts with other proteins to block immune defenses, "that wouldprovide a target for therapeutics to counteract tick-borneflaviviruses," says Dr. Best.
NIAID is a component of the National Institutes of Health, an agencyof the U.S. Department of Health and Human Services. NIAID supportsbasic and applied research to prevent, diagnose and treat infectiousdiseases such as HIV/AIDS and other sexually transmitted infections,influenza, tuberculosis, malaria and illness from potential agents ofbioterrorism. NIAID also supports research on transplantation andimmune-related illnesses, including autoimmune disorders, asthma andallergies.
Reference: S. Best et al. Inhibition of interferon-stimulatedJAK-STAT signaling by a tick-borne Flavivirus and identification of NS5as an interferon antagonist. Journal of Virology. DOI:10.1128/JVI.79.20
News releases, fact sheets and other NIAID-related materials are available on the NIAID Web site at http://www.niaid.nih.gov.
Materials provided by NIH/National Institute of Allergy and Infectious Diseases. Note: Content may be edited for style and length.
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