Discovery could be key to bioterrorism defense

Jul 30, 2005

A collaborative research team from the Uniformed Services University of the Health Sciences (USU), the Australian Animal Health Laboratory (AAHL) and the National Cancer Institute (NCI) have made a major breakthrough in efforts to combat two deadly viruses that could be engineered for use as bioweapons. The team isolated the functional receptor for the Nipah and Hendra viruses--naturally occurring and highly pathogenic paramyxoviruses for which no treatments or vaccines are currently available.

Christopher C. Broder, Ph.D., associate professor in USU's Department of Microbiology, and his NIH-funded team of researchers and investigators demonstrated that a cell surface protein called Ephrin-B2 is a functional receptor for both the Hendra and Nipah viruses. Many animal species are vulnerable to these viruses, making the potential for amplification in intermediate hosts and transmission greater. Ephrin-B2 is highly conserved in animals, and this finding sheds light on how these viruses can infest such a wide range of hosts.

"In addition to our concern about Nipah and Hendra viruses as emerging global health and economic threats, we worry about their potential use as bioterror agents," stated Anthony S. Fauci, M.D., director of the National Institute of Allergy and Infectious Diseases, the arm of NIH that funded the research, in an NIH news release. "This work, funded through our biodefense research program, is a major step towards developing countermeasures to prevent and treat Nipah and Hendra viruses."

"Now that we've identified the cell receptor, we have a new target for activity, hopefully blocking the viruses from infecting cells," Dr. Broder explained. Team members Matthew Bonaparte, Ph.D., and Anthony Dimitrov, Ph.D., both at USU, identified the cell receptor by analyzing a human cell line that was resistant to virus infection against two susceptible cell lines. The results of the research were published in the July 26 edition of the Proceedings of the National Academy of Sciences.

"We identified genes that are coded for known and predicted cell surface proteins that were missing from the resistant cell line," Dr. Broder said. "The genes were put into cells that were then exposed to a live virus at AAHL."

Hendra virus was first isolated in 1994 when an outbreak of respiratory and neurologic disease emerged among horses and humans in Hendra, Australia, killing two people. Hendra recently reemerged in Queensland, Australia, and researchers there isolated the virus at the biosafety level 4 facility.

Nipah virus, which is similar to and in the same genus as Hendra, was initially isolated in 1999, when a large outbreak of encephalitis and respiratory illness occurred in Malaysia and Singapore, killing more than 100 people. Last year, two further Nipah virus outbreaks occurred in Bangladesh, killing roughly 75% of those infected. Scientists are disturbed by the fact that many of these recent cases involved human-to-human transmission of Nipah, which originates in bats.

Ephrin-B2 is found on cells in the central nervous system, as well as in cells lining blood vessels. It is essential for central nervous system development and blood vessel growth in the embryos of humans and other mammals.

Broder and his team are among only a handful of scientists focusing on the viruses, which have been under investigation by USU researchers since 2000. Broder is a principal investigator on one of six projects from the Mid-Atlantic Regional Centers of Excellence for Biodefense and Emerging Infectious Diseases funded by NIH.

The research has led to two inventions on which USU and the Henry M. Jackson Foundation for the Advancement of Military Medicine have filed patent applications.

The first patent application, "Soluble forms of Hendra Virus and Nipah Virus G glycoprotein," covers the production and use of the soluble G glycoprotein. This protein has utility as a vaccine, in the development of pharmaceutical compositions and in diagnostic assays. The second patent application, "Compositions and Methods for the Inhibition of Membrane Fusion by Paramyxoviruses," covers the use of a novel peptide sequence of the soluble F glycoprotein, to block fusion of the virus with the host cell. This peptide can be used as a prophylactic, and/or to treat infections, and antibodies developed using this peptide can be utilized in diagnostic assays.

Source: Henry M. Jackson Foundation for the Advancement of Military Medicine

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