Forum for Science, Industry and Business

Sponsored by:     3M 
Search our Site:

 

Dengue Virus Reveals Its Circular Secret

02.08.2006
The first step in the transmission of mosquito-borne viruses is no mystery: it's the pesky insect's bite that allows the virus to enter its victim's bloodstream. But for some of the most dangerous insect-borne viruses, details of what happens next have been unclear.

In a finding that could help scientists develop ways to prevent or treat certain infections, researchers led by a Howard Hughes Medical Institute (HHMI) international scholar in Argentina have identified a genetic element that the dengue virus uses to replicate, triggering the potentially fatal illness known as dengue hemorrhagic fever.

In the August 15, 2006, issue of the journal Genes & Development, published online August 1, 2006, virologist Andrea Gamarnik and colleagues at Leloir Institute Foundation in Buenos Aires, describe how a viral enzyme recognizes and amplifies the genetic material needed to assemble new dengue viruses. Their findings provide the first model for RNA replication in the family of viruses that includes West Nile, St. Louis encephalitis, and hepatitis C.

These viruses, known as flaviviruses, cause millions of cases of human illness each year, but no vaccines or antiviral drugs exist to control most of the infections. Dengue fever is endemic in many tropical and subtropical regions, causing a severe, flu-like illness that sickens more than 50 million people and kills 25,000 each year.

Once a virus enters a host cell, its top priority is to copy its genetic code so that it can make more virus. Flaviviruses are so efficient at this task that they can churn out tens of thousands of copies of their genome—which is composed of ribonucleic acid, or RNA—within hours of infecting a cell.

For dengue and other flaviviruses, the first step is to produce viral proteins, including an enzyme that can copy RNA. But the viral RNA is not the only RNA in an infected cell. So once the enzyme, called RNA-dependent RNA polymerase (RdRp), is produced, it finds itself surrounded by cellular RNA, creating a dilemma: How does RdRp distinguish viral from cellular RNA, to replicate the right molecule?

Last year, Gamarnik got her first hint when her group identified two RNA sequences located at the ends of the dengue virus genome. These short sequences interact during RNA replication, shaping the viral RNA genome into a circle. Gamarnik's team published those findings in the June 2005 issue of the Journal of Virology.

Further studies of the dengue virus life cycle revealed another piece of the virus's RNA that recruits the enzyme RdRp. Found at one tip of the genome, that sequence adopts a characteristic stem-loop structure that the scientists suspected might be important to its function.

To test whether RdRp was relying on that stem-loop shape to recognize the viral RNA, the scientists created copies of the dengue genome with minor changes that would alter its structures. The mutated RNAs were then inserted into mosquito cells or hamster cells to see if the viral RNA would be copied.

To their surprise, the scientists found that the stem-loop or SLA sequence is essential for viral replication. Changes in even one or two building blocks in this structure were enough to halt the replication process. "That told us that RdRp probably discriminates the viral RNA by recognizing SLA," Gamarnik said.

To confirm the vital link between RdRp and SLA, the researchers allowed virus particles that couldn't replicate to evolve in cells grown in lab dishes. Spontaneous mutations that occurred in the SLA often restored RdRp's activity and full viral replication capacity.

The scientists didn't expect to find that RdRp activity relies on a sequence at the far end of the genome, thousands of nucleotides away from the end where the enzyme begins copying the RNA.

The new discovery makes sense, Gamarnik said, because the circular shape adopted by the virus brings the distant ends of its genome together. "At first we were puzzled by the cyclization feature of this virus,” said Gamarnik. "We now recognize that it serves a role in bringing the SLA promoter near the initiation site."

Paul Ahlquist, an HHMI investigator at the University of Wisconsin–Madison and an expert on RNA viruses, said that the Gamarnik team's findings explain prior observations from her lab and others that binding between the 5-prime and 3-prime ends of the viral genome is required for replication of dengue and several other medically important flaviviruses. "These insights suggest possible mechanisms by which flaviviruses may regulate some distinct replication steps, and might ultimately provide foundations for new antiflavivirus strategies," Ahlquist said.

Jennifer Donovan | EurekAlert!
Further information:
http://www.hhmi.org

More articles from Life Sciences:

nachricht Meadows beat out shrubs when it comes to storing carbon
23.11.2017 | Norwegian University of Science and Technology

nachricht Migrating Cells: Folds in the cell membrane supply material for necessary blebs
23.11.2017 | Westfälische Wilhelms-Universität Münster

All articles from Life Sciences >>>

The most recent press releases about innovation >>>

Die letzten 5 Focus-News des innovations-reports im Überblick:

Im Focus: New proton record: Researchers measure magnetic moment with greatest possible precision

High-precision measurement of the g-factor eleven times more precise than before / Results indicate a strong similarity between protons and antiprotons

The magnetic moment of an individual proton is inconceivably small, but can still be quantified. The basis for undertaking this measurement was laid over ten...

Im Focus: Frictional Heat Powers Hydrothermal Activity on Enceladus

Computer simulation shows how the icy moon heats water in a porous rock core

Heat from the friction of rocks caused by tidal forces could be the “engine” for the hydrothermal activity on Saturn's moon Enceladus. This presupposes that...

Im Focus: Nanoparticles help with malaria diagnosis – new rapid test in development

The WHO reports an estimated 429,000 malaria deaths each year. The disease mostly affects tropical and subtropical regions and in particular the African continent. The Fraunhofer Institute for Silicate Research ISC teamed up with the Fraunhofer Institute for Molecular Biology and Applied Ecology IME and the Institute of Tropical Medicine at the University of Tübingen for a new test method to detect malaria parasites in blood. The idea of the research project “NanoFRET” is to develop a highly sensitive and reliable rapid diagnostic test so that patient treatment can begin as early as possible.

Malaria is caused by parasites transmitted by mosquito bite. The most dangerous form of malaria is malaria tropica. Left untreated, it is fatal in most cases....

Im Focus: A “cosmic snake” reveals the structure of remote galaxies

The formation of stars in distant galaxies is still largely unexplored. For the first time, astron-omers at the University of Geneva have now been able to closely observe a star system six billion light-years away. In doing so, they are confirming earlier simulations made by the University of Zurich. One special effect is made possible by the multiple reflections of images that run through the cosmos like a snake.

Today, astronomers have a pretty accurate idea of how stars were formed in the recent cosmic past. But do these laws also apply to older galaxies? For around a...

Im Focus: Visual intelligence is not the same as IQ

Just because someone is smart and well-motivated doesn't mean he or she can learn the visual skills needed to excel at tasks like matching fingerprints, interpreting medical X-rays, keeping track of aircraft on radar displays or forensic face matching.

That is the implication of a new study which shows for the first time that there is a broad range of differences in people's visual ability and that these...

All Focus news of the innovation-report >>>

Anzeige

Anzeige

Event News

Ecology Across Borders: International conference brings together 1,500 ecologists

15.11.2017 | Event News

Road into laboratory: Users discuss biaxial fatigue-testing for car and truck wheel

15.11.2017 | Event News

#Berlin5GWeek: The right network for Industry 4.0

30.10.2017 | Event News

 
Latest News

Lightning, with a chance of antimatter

24.11.2017 | Earth Sciences

A huge hydrogen generator at the Earth's core-mantle boundary

24.11.2017 | Earth Sciences

Scientists find why CP El Niño is harder to predict than EP El Niño

24.11.2017 | Earth Sciences

VideoLinks
B2B-VideoLinks
More VideoLinks >>>