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December 9, 2002

West Nile Virus Capsid Protein Causes Encephalitic Inflammation by Triggering Cell Suicide

(Philadelphia, 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 organ transplantations.

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 Nile."

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.


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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: www.cdc.gov/ncidod/eid/

 

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