Scientists find potential Achilles' heel on Lassa fever and related viruses

November 15, 2011
Scientists at the Scripps Research Institute have determined the atomic structure of a protein that the Lassa fever virus uses to make copies of itself within infected cells. This surface representation of the nucleoprotein shows the RNA bound in between the two sub-domains, highlighting, in particular, a deep pocket that could be a prime target for antivirals. Credit: Photo courtesy of the Ollmann Saphire lab, The Scripps Research Institute.

Scientists at The Scripps Research Institute have determined the atomic structure of a protein that the Lassa fever virus uses to make copies of itself within infected cells. The structural data reveal an unexpected molecular crevice where the viral protein grips the viral genes, making this crevice a target for potential antiviral drugs. Lassa fever virus and other arenaviruses infect hundreds of thousands of people annually and are often deadly. Currently there is no specific therapy or vaccine against them.

"It's the first look we've ever had at an nucleoprotein bound to its genome, and so it opens up many new research pathways, and of course gives us a clear aiming point for the development of anti-arenavirus drugs," said Erica Ollmann Saphire, associate professor in Scripps Research's Department of Immunology and Microbial Science. Ollmann Saphire is the senior author of the new report, which appears in an early online edition of the the week of November 14, 2011.

The arenavirus nucleoprotein serves in part as a to hold the viral RNA-based genome while it is translated into new viral proteins. Blocking the nucleoprotein's interaction with the would prevent an arenavirus from replicating itself–and thus should stop the course of an infection.

A separate team of structural biologists reported the of the Lassa fever virus nucleoprotein–considered typical of arenavirus nucleoproteins–in 2010. But until now, no one had determined the nucleoprotein structure while bound to . "These nucleoproteins can be tricky to work with, because they do bind so easily to RNA or even to themselves," said Kathryn Hastie, a PhD candidate in the Ollmann Saphire lab who performed most of the experiments and is the lead author of the report.

Hastie produced a shortened version of the Lassa fever virus nucleoprotein and, in this way, was able to crystallize it while it was bound to a segment of viral RNA. When a molecule has been crystallized, researchers can beam X-rays at it, record the resulting diffraction patterns, and infer the molecule's 3-D atomic structure.

In this case, the high-resolution structural data revealed the crucial site where the nucleoprotein binds to viral RNA. Previous studies of nucleoproteins from other RNA viruses had predicted the RNA-binding site would be in a central region of the nucleoprotein. However, Hastie, Ollmann Saphire and their colleagues found instead that the Lassa fever virus RNA binding site is within a cleft at one end of the nucleoprotein. "This end of the nucleoprotein is shaped like a clamshell, and in the X-ray diffraction imagery we observed a big strip of positive density sitting between the two halves of the clamshell, which we could identify as RNA," said Hastie.

The structural data and follow up studies indicated that the nucleoprotein normally exists in a "trimer" formation, in which three lengths of the protein are linked in a rough triangle. In this formation, the RNA binding site is normally blocked, but an encounter with another or some other trigger may "unlock" the trimer formation and expose the RNA binding site.

The Ollmann Saphire lab now is investigating the precise sequence of molecular events that causes the viral nucleoprotein to bind to viral RNA. But it is already clear, for example, that getting a drug into the cleft where the nucleoprotein binds RNA should block RNA-binding and thus stop the virus from replicating. Such a drug might work not only against Lassa fever virus but against other arenaviruses, too. "The part of the Lassa fever virus nucleoprotein that contacts the RNA is exactly the same for every other arenavirus, so it's highly likely that this is how the other arenaviruses bind their RNA," Hastie said.

Ollmann Saphire is now looking for a pharmaceutical company partner to help her lab turn the new finding into a candidate anti-arenavirus drug and to test it clinically.

Lassa fever virus is endemic in parts of West Africa, where its natural host is a local mouse species. It infects 300,000 to 500,000 people and kills at least several thousand of them annually, according to the Centers for Disease Control. At least five other arenaviruses–Junín, Machupo, Guanarito, Chapare and Sabiá–are found in South America and can cause fatal hemorrhagic fevers. Arenaviruses in North America include the meningitis-associated lymphocytic choriomeningitis virus, which also can silently infect pregnant women and cause birth defects. A recent study found antibodies to arenaviruses in the blood of about 3.5 percent of US patients with neurologic symptoms or fevers of unknown origin.

Arenaviruses usually spread to humans from their rodent host population, but there is evidence that they can spread from human to human, and occasionally they cause large outbreaks of fatal disease. The antiviral drug ribavirin has been used to treat arenavirus disease, but seems to help only modestly, and only when administered in early stages of infection.

"Arenaviruses are a huge class of human pathogens that exist almost worldwide, and they are circulating and evolving continuously in a rodent population that we can never eradicate," says Ollmann Saphire. "We don't know which arenaviruses are only one or two mutations away from causing a major disease outbreak. And up to now we have no real defense against them."

Explore further: New drug could combat killer diseases

More information: "Crystal structure of the Lassa virus nucleoprotein–RNA complex reveals a gating mechanism for RNA binding," Proceedings of the National Academy of Sciences (2011).

Related Stories

New drug could combat killer diseases

September 30, 2011
(Medical Xpress) -- Researchers from the University of Reading have developed a new drug which could reduce the spread of deadly diseases such as Lassa Fever and Aseptic Meningitis.

Research provides unprecedented insight into fighting viral infections

September 29, 2011
Researchers at Rutgers and UMDNJ-Robert Wood Johnson Medical School have determined the structure of a protein that is the first line of defense in fighting viral infections including influenza, hepatitis C, West Nile, rabies, ...

Recommended for you

Surprising roles for muscle in tissue regeneration, study finds

November 22, 2017
A team of researchers at Whitehead has illuminated an important role for different subtypes of muscle cells in orchestrating the process of tissue regeneration. In a paper published in the November 22 issue of Nature, they ...

Study reveals new mechanisms of cell death in neurodegenerative disorders

November 22, 2017
Researchers at King's College London have discovered new mechanisms of cell death, which may be involved in debilitating neurodegenerative disorders, such as Alzheimer's disease and Parkinson's disease.

How rogue immune cells cross the blood-brain barrier to cause multiple sclerosis

November 21, 2017
Drug designers working on therapeutics against multiple sclerosis should focus on blocking two distinct ways rogue immune cells attack healthy neurons, according to a new study in the journal Cell Reports.

New simple test could help cystic fibrosis patients find best treatment

November 21, 2017
Several cutting-edge treatments have become available in recent years to correct the debilitating chronic lung congestion associated with cystic fibrosis. While the new drugs are life-changing for some patients, they do not ...

Researchers discover key signaling protein for muscle growth

November 20, 2017
Researchers at the University of Louisville have discovered the importance of a well-known protein, myeloid differentiation primary response gene 88 (MyD88), in the development and regeneration of muscles. Ashok Kumar, Ph.D., ...

New breast cell types discovered by multidisciplinary research team

November 20, 2017
A joint effort by breast cancer researchers and bioinformaticians has provided new insights into the molecular changes that drive breast development.


Please sign in to add a comment. Registration is free, and takes less than a minute. Read more

Click here to reset your password.
Sign in to get notified via email when new comments are made.