SCIENTISTS DISCOVER HOW NIPAH VIRUS ENTERS CELLS
Working independently, two research teams funded by the National Institute
of Allergy and Infectious Diseases (NIAID), part of the National Institutes
of Health (NIH), have identified how Nipah and Hendra viruses, closely
related viruses first identified in the mid-1990s, gain entry into human and
animal cells.
Nipah and Hendra are emerging viruses that cause serious respiratory and
neurological disease. People can get these deadly viruses from animals.
Beginning in 1994, public health officials have recognized disease outbreaks
in Malaysia, Singapore, Bangladesh and Australia.
Both viruses use a protein essential to embryonic development to enter cells
and begin their often-fatal attack, report researchers at the University of
California, Los Angeles (UCLA) and the Uniformed Services University of the
Health Sciences (USUHS) in Bethesda, Maryland.
The UCLA team, headed by Benhur Lee, M.D., describes its findings in a
"Nature" paper posted online on July 6. The report by the USUHS researchers,
led by Christopher Broder, Ph.D., is appearing online the week of July 4 in
the "Proceedings of the National Academy of Sciences".
The first reported outbreak of Nipah virus occurred in 1998-1999 in
Malaysia, sickening 265 people and killing 105, according to the World
Health Organization. This outbreak, which in this case spread from pigs to
humans, was contained by culling more than a million pigs. Hendra virus, so
far less of a threat to human health, was first identified in 1994 in
Australia when it spread from horses to humans.
"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," says Anthony S. Fauci, M.D., director of NIAID. "This
work, funded through our biodefense research program, is a major step
towards developing countermeasures to prevent and treat Nipah and Hendra
infection."
Using different methods, both teams identified a specific cell surface
receptor, Ephrin-B2, as the doorway used by Nipah and Hendra viruses to get
inside cells. This receptor is found on cells in the central nervous system
and those lining blood vessels. It is crucial for the normal development of
the nervous system and the growth of blood vessels in human and other animal
embryos. Ephrin-B2 is found in humans, horses, pigs, bats and other mammals,
which explains the unusually broad range of species susceptible to Nipah and
Hendra virus infection.
Dr. Broder and his colleagues collaborated with researchers at the National
Cancer Institute, also part of the NIH, and the Australian Animal Health
Laboratory. The team narrowed the search for the Nipah/Hendra receptor by
first sifting through the genetic sequences of 55,000 possible receptors
using microarray technology as a molecular "sieve."
The scientists compared microarray signals from the 55,000 genetic sequences
in one set of Nipah virus-resistant human cells with microarray signals from
three sets of human cells that the virus can infect. This enabled the
research team to narrow the possible number of receptor proteins to 120 by
identifying those present in the virus-susceptible cells but absent in the
virus-resistant cells. They winnowed the possibilities further -- to just 21
-- by selecting only those candidate receptors within the molecular weight
range they expected. They selected 10 expressed at high levels in the
susceptible cell lines and inserted them, one by one, into the cells that
resisted Nipah virus to identify the receptor. When they inserted the gene
for Ephrin-B2, the previously Nipah-resistant cells admitted the virus.
The UCLA team, with collaborators at the University of Pennsylvania, took a
different approach, using tools of advanced molecular biology as well as
old-fashioned detective work to identify the Ephrin-B2 receptor. They knew
the receptor would be abundant among the type of cells Nipah virus attacks,
that is, nerve cells and cells lining blood vessels.
To identify the human cell receptor, they created a bait: the Nipah protein
that docks to that unknown receptor was attached to part of a human
antibody, like a worm on a fishing hook. When they placed this bait onto
cells susceptible to Nipah virus infection, it attached to a protein on the
cell surface. When placed on Nipah-resistant cells, however, the antibody
did not attach to the cells. The scientists used an instrument that sorts
molecules by weight to identify that Ephrin-B2 was the cell receptor protein
that bound to the antibody/Nipah protein "fishing pole" they had made.
They wanted to confirm their findings, but since they did not have access to
a high-level biosafety laboratory as Dr. Broder's team did, the UCLA
researchers engineered a harmless virus with Nipah virus proteins embedded
in its coat. The UCLA team found that this artificial construct could infect
cells vulnerable to Nipah virus but was unable to infect Nipah
virus-resistant cells. They also showed that this engineered virus could
infect nerve cells and cells lining blood vessels using Ephrin-B2 as the
receptor, in the same way as actual Nipah virus would infect these cells.
Knowing the identity of the Nipah and Hendra receptor will not only help in
developing vaccines and treatments, but also promises to lead to better
understanding of how the viruses cause disease in people and a variety of
animals, the researchers say.
NIAID is a component of the National Institutes of Health, an agency of the
U.S. Department of Health and Human Services. NIAID supports basic and
applied research to prevent, diagnose and treat infectious diseases such as
HIV/AIDS and other sexually transmitted infections, influenza, tuberculosis,
malaria and illness from potential agents of bioterrorism. NIAID also
supports research on transplantation and immune-related illnesses, including
autoimmune disorders, asthma and allergies.
News releases, fact sheets and other NIAID-related materials are available
on the NIAID Web site at http://www.niaid.nih.gov.
The National Institutes of Health (NIH) - The Nation's Medical Research
Agency - is comprised of 27 Institutes and Centers and is a component of the
U. S. Department of Health and Human Services. It is the primary Federal
agency for conducting and supporting basic, clinical, and translational
medical research, and investigates the causes, treatments, and cures for
both common and rare diseases. For more information about NIH and its
programs, visit www.nih.gov.
__________
References: MI Bonaparte et al. Ephrin-B2 ligand is a functional receptor
for Hendra virus and Nipah virus. "Proceedings of the National Academy of
Sciences" vol 102 (2005) doi:10.1073/pnas/0504887102.
OA Negrete et al. Ephrin B2 is the entry receptor for Nipah virus, an
emergent deadly paramyxovirus. "Nature" (2005) doi: 10.1038/nature03838.
__________
of Allergy and Infectious Diseases (NIAID), part of the National Institutes
of Health (NIH), have identified how Nipah and Hendra viruses, closely
related viruses first identified in the mid-1990s, gain entry into human and
animal cells.
Nipah and Hendra are emerging viruses that cause serious respiratory and
neurological disease. People can get these deadly viruses from animals.
Beginning in 1994, public health officials have recognized disease outbreaks
in Malaysia, Singapore, Bangladesh and Australia.
Both viruses use a protein essential to embryonic development to enter cells
and begin their often-fatal attack, report researchers at the University of
California, Los Angeles (UCLA) and the Uniformed Services University of the
Health Sciences (USUHS) in Bethesda, Maryland.
The UCLA team, headed by Benhur Lee, M.D., describes its findings in a
"Nature" paper posted online on July 6. The report by the USUHS researchers,
led by Christopher Broder, Ph.D., is appearing online the week of July 4 in
the "Proceedings of the National Academy of Sciences".
The first reported outbreak of Nipah virus occurred in 1998-1999 in
Malaysia, sickening 265 people and killing 105, according to the World
Health Organization. This outbreak, which in this case spread from pigs to
humans, was contained by culling more than a million pigs. Hendra virus, so
far less of a threat to human health, was first identified in 1994 in
Australia when it spread from horses to humans.
"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," says Anthony S. Fauci, M.D., director of NIAID. "This
work, funded through our biodefense research program, is a major step
towards developing countermeasures to prevent and treat Nipah and Hendra
infection."
Using different methods, both teams identified a specific cell surface
receptor, Ephrin-B2, as the doorway used by Nipah and Hendra viruses to get
inside cells. This receptor is found on cells in the central nervous system
and those lining blood vessels. It is crucial for the normal development of
the nervous system and the growth of blood vessels in human and other animal
embryos. Ephrin-B2 is found in humans, horses, pigs, bats and other mammals,
which explains the unusually broad range of species susceptible to Nipah and
Hendra virus infection.
Dr. Broder and his colleagues collaborated with researchers at the National
Cancer Institute, also part of the NIH, and the Australian Animal Health
Laboratory. The team narrowed the search for the Nipah/Hendra receptor by
first sifting through the genetic sequences of 55,000 possible receptors
using microarray technology as a molecular "sieve."
The scientists compared microarray signals from the 55,000 genetic sequences
in one set of Nipah virus-resistant human cells with microarray signals from
three sets of human cells that the virus can infect. This enabled the
research team to narrow the possible number of receptor proteins to 120 by
identifying those present in the virus-susceptible cells but absent in the
virus-resistant cells. They winnowed the possibilities further -- to just 21
-- by selecting only those candidate receptors within the molecular weight
range they expected. They selected 10 expressed at high levels in the
susceptible cell lines and inserted them, one by one, into the cells that
resisted Nipah virus to identify the receptor. When they inserted the gene
for Ephrin-B2, the previously Nipah-resistant cells admitted the virus.
The UCLA team, with collaborators at the University of Pennsylvania, took a
different approach, using tools of advanced molecular biology as well as
old-fashioned detective work to identify the Ephrin-B2 receptor. They knew
the receptor would be abundant among the type of cells Nipah virus attacks,
that is, nerve cells and cells lining blood vessels.
To identify the human cell receptor, they created a bait: the Nipah protein
that docks to that unknown receptor was attached to part of a human
antibody, like a worm on a fishing hook. When they placed this bait onto
cells susceptible to Nipah virus infection, it attached to a protein on the
cell surface. When placed on Nipah-resistant cells, however, the antibody
did not attach to the cells. The scientists used an instrument that sorts
molecules by weight to identify that Ephrin-B2 was the cell receptor protein
that bound to the antibody/Nipah protein "fishing pole" they had made.
They wanted to confirm their findings, but since they did not have access to
a high-level biosafety laboratory as Dr. Broder's team did, the UCLA
researchers engineered a harmless virus with Nipah virus proteins embedded
in its coat. The UCLA team found that this artificial construct could infect
cells vulnerable to Nipah virus but was unable to infect Nipah
virus-resistant cells. They also showed that this engineered virus could
infect nerve cells and cells lining blood vessels using Ephrin-B2 as the
receptor, in the same way as actual Nipah virus would infect these cells.
Knowing the identity of the Nipah and Hendra receptor will not only help in
developing vaccines and treatments, but also promises to lead to better
understanding of how the viruses cause disease in people and a variety of
animals, the researchers say.
NIAID is a component of the National Institutes of Health, an agency of the
U.S. Department of Health and Human Services. NIAID supports basic and
applied research to prevent, diagnose and treat infectious diseases such as
HIV/AIDS and other sexually transmitted infections, influenza, tuberculosis,
malaria and illness from potential agents of bioterrorism. NIAID also
supports research on transplantation and immune-related illnesses, including
autoimmune disorders, asthma and allergies.
News releases, fact sheets and other NIAID-related materials are available
on the NIAID Web site at http://www.niaid.nih.gov.
The National Institutes of Health (NIH) - The Nation's Medical Research
Agency - is comprised of 27 Institutes and Centers and is a component of the
U. S. Department of Health and Human Services. It is the primary Federal
agency for conducting and supporting basic, clinical, and translational
medical research, and investigates the causes, treatments, and cures for
both common and rare diseases. For more information about NIH and its
programs, visit www.nih.gov.
__________
References: MI Bonaparte et al. Ephrin-B2 ligand is a functional receptor
for Hendra virus and Nipah virus. "Proceedings of the National Academy of
Sciences" vol 102 (2005) doi:10.1073/pnas/0504887102.
OA Negrete et al. Ephrin B2 is the entry receptor for Nipah virus, an
emergent deadly paramyxovirus. "Nature" (2005) doi: 10.1038/nature03838.
__________
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