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UCLA scientists have discovered how the deadly Nipah virus infiltrates human cells to cause encephalitis. Designated as a potential bioterrorism agent by the National Biodefense Research Agenda, the virus exploits a protein essential to embryonic development to enter cells and launch its attack. The online edition of Nature reports the findings July 6.
In its natural state, the Nipah virus can be used as a potential bioterrorism agent capable of devastating an entire countrys public health and economy, said Dr. Benhur Lee, principal investigator and UCLA assistant professor of microbiology, immunology and molecular genetics. Now that we understand how the virus operates, we can develop vaccines and drugs to block Nipah from entering the cells. This will help prevent infection and halt outbreaks before they reach epidemic proportions.
Since 1998, the Nipah virus has triggered disease outbreaks in Australia, Singapore, Malaysia and Bangladesh. Animals spread the virus to people, where it causes life-threatening respiratory and neurological diseases that kill up to 70 percent of patients a danger level equivalent to the Ebola virus.
To infect a cell, viruses must bind to a viral-specific receptor on the cells surface in order to penetrate it. Lees team identified a cell receptor called Ephrin-B2 as the key used by the Nipah virus to unlock the cells.
Located on brain cells and cells lining the blood vessels, Ephrin-B2 is critical to nervous system development and the growth of blood vessels in human and animal embryos. Ephrin-B2 is found in humans, horses, pigs and bats, which may explain why the infection can jump so easily from one species to another.
Collaborating with the University of Pennsylvania, the UCLA team applied tools of advanced molecular biology as well as old-fashioned detective work to track down the identity of the Ephrin-B2 receptor.
The researchers created a bait: they stitched the Nipah protein to part of a human antibody, like a worm on a fishing hook. When they placed this bait on cells at risk for Nipah infection, the antibody attached to a receptor on the cell surface. When placed on Nipah-resistant cells, however, the bait did not bind to the cell.
The scientists used an instrument that sorts molecules by weight to identify Ephrin-B2 as the receptor that bound to the bait.
To confirm their findings, the UCLA team engineered a harmless virus with Nipah virus proteins embedded in its coat. The decoy virus successfully infected cells vulnerable to the Nipah virus, but could not infect Nipah-resistant cells.
In the final step, the decoy virus entered nerve cells and cells lining blood vessels by latching onto Ephrin-B2, proving that the receptor is the same doorway that the real Nipah virus enters to infect these cells.
We now can screen for small molecules that will block viral entry via Ephrin B-2 and develop them as therapeutic drugs, said Lee. Because pigs are particularly susceptible to Nipah infection, public health officials could use these drugs to protect the animals, pig farmers and first-line responders, like paramedics, from a Nipah virus outbreak.
In the United States, agricultural experts estimate the value of pigs alone in the hog-farming industry at $8.6 billion.
The first reported outbreak of Nipah virus in Malaysia occurred between 1998 and 1999, sickening 265 people and killing 105. Spread from bats to pigs to humans, the outbreak infected more than 200 pig farmers and killed 40 percent. Desperate to contain the outbreak, the government ordered its military to kill more than 1 million pigs, resulting in economic devastation to the country.
In Bangladesh, death rates of repeated outbreaks of Nipah virus in the past four years have risen to 70 percent, suggesting that the virus is growing more lethal.
The National Institute of Allergy and Infectious Diseases funded the study.
Lees coauthors included Oscar Negrete, Ernest Levroney, Hector Aguilar, Ronen Nazarian and Sara Tajyar of the David Geffen School of Medicine at UCLA, and Andrea Bertolotti-Ciarlet of the University of Pennsylvania.