PA) - The protein that forms the protective capsid surrounding
the West Nile virus genetic material may contribute
to the deadly inflammation associated with the virus.
West Nile virus, which has rapidly spread across the
United States, causes neurological symptoms and encephalitis,
which can result in paralysis or death. According to
researchers at the University of Pennsylvania School
of Medicine, the West Nile virus capsid (WNV-Cp)
is a destructive protein that can trigger apoptosis
- the automatic self-destructive program within cells
- inside infected cells, possibly adding to the damage
caused by the virus. Their findings are presented in
the December issue of Emerging Infectious Diseases,
a journal available on the Centers for Disease Control
and Prevention (CDC) Web site. (See Editor's Note,
below for URL)
"Despite the fact that West Nile virus is a global
health threat, we understand very little of the pathogenesis
of the disease caused by this virus," said David
Weiner, PhD, associate professor in Penn's Department
of Pathology and Laboratory Medicine. "Since there
is currently no specific treatment for West Nile virus,
it is important to understand the biology of this virus
to help us devise vaccines and new treatments for the
West Nile virus infection."
According to the CDC, the West Nile virus has infected
over 3700 people and killed over 200, mostly elderly,
people since it was first introduced to the United States
in 1999. The numbers of those infected, however, may
be much higher since the disease often takes a mild
form in healthy people who are less likely to seek treatment
and the CDC numbers only count for those cases known
to state medical agencies. The virus is spread primarily
through its insect host, the mosquito, although it is
now known to spread through mothers' breast milk and
The Penn researchers first began studying WNV-Cp when
they noticed a striking similarity between the gene
that encodes for it and that of an HIV regulatory protein.
"We hope to extend the lessons they have learned
in trying to develop therapeutics for HIV in fighting
West Nile." Said Weiner. "In addition to the
possibility of creating a vaccine for West Nile, our
results support the idea that a specific portion of
the capsid protein - called the 3' terminal region -
is required for the protein's pathogenicity. If we can
find a way to block that region's function, this might
help slow the virus down."
By itself, the WNV-Cp protein can cause inflammation.
Weiner and his colleagues found that WNV-Cp drives apoptosis
in cell cultures through what is called the mitochondrial
pathway. The protein begins the process of cell suicide
by somehow disrupting the membrane potential of the
cell's mitochondria, which then leads to the activation
of proteins such as caspase-9 and caspase-3 that start
a cascade of reactions to subsequently cause the cell
to digest itself.
Since the protein enters the nucleus of the cell, it
is possible that WNV-Cp changes the host cell's transcriptional
machinery, resulting in an over production of certain
proteins related to an apoptotic program, which consequently
feed back to the mitochondria. Alternatively, as WNV-Cp
moves from the cytoplasm to the nucleus, it may inactivate
an important part of the cell's natural control system
that keeps apoptosis in check - overpowering the guard
as it were - thus inducing the cell suicide.
"Overall, our data suggest that WNV-Cp may interact
with host cell proteins to induce apoptosis in the host
cell," said Weiner, "Identifying these proteins
will likely give more insight into the biology of West
The proteins pathogenic properties extend outside of
the tissue culture. WNV-Cp also directly caused apoptosis
and inflammation in mouse muscle cells. More importantly,
the WNV-Cp protein caused inflammation and apoptosis
in mouse brain in a manner similar to what is observed
in natural infections.
Funding for this work was supported by grants from the
National Institutes of Health.
# # #
Editor's Note: You may find the December Emerging
Infectious Disease article, entitled 'Induction
of Inflammation by West Nile virus Capsid through the
Caspase-9 Apoptotic Pathway,' on the CDC Web site at:
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