Scientists Discover How Nipah Virus Enters Cells, = July 6, 2005 Press Release

From: Subject: Scientists Discover How Nipah Virus Enters Cells, July 6, 2005 Press Release - National Institutes of Health (NIH) Date: Fri, 4 Jan 2008 14:35:16 -0800 MIME-Version: 1.0 Content-Type: multipart/related; type="text/html"; boundary="----=_NextPart_000_0105_01C84EDF.05FB7BE0" X-MimeOLE: Produced By Microsoft MimeOLE V6.00.2900.3198 This is a multi-part message in MIME format. ------=_NextPart_000_0105_01C84EDF.05FB7BE0 Content-Type: text/html; charset="iso-8859-1" Content-Transfer-Encoding: quoted-printable Content-Location: http://www.nih.gov/news/pr/jul2005/niaid-06.htm Scientists Discover How Nipah Virus Enters Cells, = July 6, 2005 Press Release - National Institutes of Health (NIH)

National Institute of Allergy = and=20 Infectious Diseases (NIAID)

EMBARGOED FOR RELEASE
Wednesday, July 6,=20 2005
1:00 p.m. ET=20

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CONTACT:
Linda = Joy
301-402-1663=20

Scientists Discover How Nipah Virus = Enters=20 Cells=20

Working independently, two research teams funded by the = National=20 Institute of Allergy and Infectious Diseases (NIAID), part = of the=20 National Institutes of Health (NIH), have identified how = Nipah and=20 Hendra viruses, closely related viruses first identified in = the=20 mid-1990s, gain entry into human and animal cells.

Nipah and Hendra are emerging viruses that cause serious=20 respiratory and neurological disease. People can get these = deadly=20 viruses from animals. Beginning in 1994, public health = officials=20 have recognized disease outbreaks in Malaysia, Singapore, = Bangladesh=20 and Australia.

Both viruses use a protein essential to embryonic = development to=20 enter cells and begin their often-fatal attack, report = researchers=20 at the University of California, Los Angeles (UCLA) and the=20 Uniformed Services University of the Health Sciences (USUHS) = in=20 Bethesda, Maryland.

The UCLA team, headed by Benhur Lee, M.D., describes its = findings=20 in a Nature paper posted online on July 6. The = report by=20 the USUHS researchers, led by Christopher Broder, Ph.D., is=20 appearing online the week of July 4 in the Proceedings = of the=20 National Academy of Sciences.

The first reported outbreak of Nipah virus occurred in = 1998-1999=20 in Malaysia, sickening 265 people and killing 105, according = to the=20 World Health Organization. This outbreak, which in this case = spread=20 from pigs to humans, was contained by culling more than a = million=20 pigs. Hendra virus, so far less of a threat to human health, = was=20 first identified in 1994 in Australia when it spread from = horses to=20 humans.

=93In addition to our concern about Nipah and Hendra = viruses as=20 emerging global health and economic threats, we worry about = their=20 potential use as bioterror agents,=94 says Anthony S. Fauci, = M.D.,=20 director of NIAID. =93This work, funded through our = biodefense=20 research program, is a major step towards developing = countermeasures=20 to prevent and treat Nipah and Hendra infection.=94

Using different methods, both teams identified a specific = cell=20 surface receptor, Ephrin-B2, as the doorway used by Nipah = and Hendra=20 viruses to get inside cells. This receptor is found on cells = in the=20 central nervous system and those lining blood vessels. It is = crucial=20 for the normal development of the nervous system and the = growth of=20 blood vessels in human and other animal embryos. Ephrin-B2 = is found=20 in humans, horses, pigs, bats and other mammals, which = explains the=20 unusually broad range of species susceptible to Nipah and = Hendra=20 virus infection.

Dr. Broder and his colleagues collaborated with = researchers at=20 the National Cancer Institute, also part of the NIH, and the = Australian Animal Health Laboratory. The team narrowed the = search=20 for the Nipah/Hendra receptor by first sifting through the = genetic=20 sequences of 55,000 possible receptors using microarray = technology=20 as a molecular =93sieve.=94

The scientists compared microarray signals from the = 55,000=20 genetic sequences in one set of Nipah virus-resistant human = cells=20 with microarray signals from three sets of human cells that = the=20 virus can infect. This enabled the research team to narrow = the=20 possible number of receptor proteins to 120 by identifying = those=20 present in the virus-susceptible cells but absent in the=20 virus-resistant cells. They winnowed the possibilities = further =97 to=20 just 21 =97 by selecting only those candidate receptors = within the=20 molecular weight range they expected. They selected 10 = expressed at=20 high levels in the susceptible cell lines and inserted them, = one by=20 one, into the cells that resisted Nipah virus to identify = the=20 receptor. When they inserted the gene for Ephrin-B2, the = previously=20 Nipah-resistant cells admitted the virus.

The UCLA team, with collaborators at the University of=20 Pennsylvania, took a different approach, using tools of = advanced=20 molecular biology as well as old-fashioned detective work to = identify the Ephrin-B2 receptor. They knew the receptor = would be=20 abundant among the type of cells Nipah virus attacks, that = is, nerve=20 cells and cells lining blood vessels.

To identify the human cell receptor, they created a bait: = the=20 Nipah protein that docks to that unknown receptor was = attached to=20 part of a human antibody, like a worm on a fishing hook. = When they=20 placed this bait onto cells susceptible to Nipah virus = infection, it=20 attached to a protein on the cell surface. When placed on=20 Nipah-resistant cells, however, the antibody did not attach = to the=20 cells. The scientists used an instrument that sorts = molecules by=20 weight to identify that Ephrin-B2 was the cell receptor = protein that=20 bound to the antibody/Nipah protein =93fishing pole=94 they = had made.=20

They wanted to confirm their findings, but since they did = not=20 have access to a high-level biosafety laboratory as Dr. = Broder=92s=20 team did, the UCLA researchers engineered a harmless virus = with=20 Nipah virus proteins embedded in its coat. The UCLA team = found that=20 this artificial construct could infect cells vulnerable to = Nipah=20 virus but was unable to infect Nipah virus-resistant cells. = They=20 also showed that this engineered virus could infect nerve = cells and=20 cells lining blood vessels using Ephrin-B2 as the receptor, = in the=20 same way as actual Nipah virus would infect these cells. =

Knowing the identity of the Nipah and Hendra receptor = will not=20 only help in developing vaccines and treatments, but also = promises=20 to lead to better understanding of how the viruses cause = disease in=20 people and a variety of animals, the researchers say.

NIAID is a component of the National Institutes of = Health, an=20 agency of the U.S. Department of Health and Human Services. = NIAID=20 supports basic and applied research to prevent, diagnose and = treat=20 infectious diseases such as HIV/AIDS and other sexually = transmitted=20 infections, influenza, tuberculosis, malaria and illness = from=20 potential agents of bioterrorism. NIAID also supports = research on=20 transplantation and immune-related illnesses, including = autoimmune=20 disorders, asthma and allergies.

News releases, fact sheets and other NIAID-related = materials=20 are available on the NIAID Web site at http://www.niaid.nih.gov/.=20

The National Institutes of Health (NIH) =97 The = Nation's=20 Medical Research Agency =97 is comprised of 27 = Institutes and=20 Centers and is a component of the U. S. Department of Health = and=20 Human Services. It is the primary Federal agency for = conducting and=20 supporting basic, clinical, and translational medical = research, and=20 investigates the causes, treatments, and cures for both = common and=20 rare diseases. For more information about NIH and its = programs,=20 visit www.nih.gov.=20

References: MI Bonaparte et al. Ephrin-B2 = ligand is=20 a functional receptor for Hendra virus and Nipah virus.=20 Proceedings of the National Academy of Sciences vol = 102=20 (2005) doi:10.1073/pnas/0504887102.=20

OA Negrete et al. Ephrin B2 is the entry = receptor for=20 Nipah virus, an emergent deadly paramyxovirus. = Nature=20 (2005) doi: 10.1038/nature03838. =

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