|Scientists Show that Tick-Borne Flaviviruses Use a Novel Mechanism
to Evade Host Defenses
Researchers from the National Institute of Allergy and Infectious Diseases
(NIAID), part of the National Institutes of Health, have made the surprising
discovery that flaviviruses, which cause such serious diseases as West Nile fever,
yellow fever and forms of encephalitis, evade immune system defenses in different
ways depending on whether they are transmitted by mosquitoes or ticks. This finding
could lead to new approaches to developing vaccines and treatments against these
“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.
News releases, fact sheets and other NIAID-related materials are available on
the NIAID Web site at http://www.niaid.nih.gov.
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.
The National Institutes of Health (NIH) — The Nation's Medical Research
Agency — includes 27 Institutes and Centers and is a component of
the U. S. Department of Health and Human Services. It is the primary Federal
agency for conducting and supporting basic, clinical, and translational medical
research, and it investigates the causes, treatments, and cures for both common
and rare diseases. For more information about NIH and its programs, visit http://www.nih.gov.