Re: Deaths From WNV May Be Tied to a Gene Variation

<x-flowed iso-8859-1>If this is true for birds also, it could the reason for the apparent
absence of the effect "dead birds" of the West Nile virus within
regions, like Europe, where it is circulating since long ago...
For me, the most striking thing since the introduction of the virus
in the New World, is the incredible bird rate. In Romania we cannot
use birds death as an indicator of WN virus activity.
Cornelia Ceianu, PhD
Vector Borne Diseases Reference Center
Cantacuzino Institute
Bucarest, Romania

Environmental Risk Analysis Program wrote:

>1) Research on WNV fatalities correlates with mice gene variation
>(Associated Press, Aug 20, 2002)
>
>2) Abstract of research article on which the news story is based,
>Proceedings of the National Academy of Sciences, Aug 20, 2002
>
>
>1) DEATHS from WEST NILE VIRUS MAY BE TIED to a GENE VARIATION [edited]
> August 20, 2002
> By THE ASSOCIATED PRESS
>
>WASHINGTON, Aug. 19 (AP) - Only about one in five people infected
>with the West Nile virus develops a life-threatening illness, and a
>new study in mice suggests that a gene variation may be the reason
>some become very sick from the mosquito-borne virus while others
>recover easily.
>
>Experts say the research is an important step toward finding a drug
>to treat West Nile, a virus that has caused 11 deaths in the United
>States this year.
>
> ...SNIP...
>
>Scientists at the Pasteur Institute in France searched for a gene
>variation that might explain the difference in susceptibility.
>
>The French first tested a series of laboratory mouse strains to find
>a genetic type that was most likely to die after being exposed to
>the West Nile virus.
>
>They found that animals in the mouse strain called BALB/c all died
>within 13 days when injected with the West Nile virus. When these
>animals were mated with other mouse strains, some of the offspring
>died from the virus, while others were little affected.
>
>By analyzing the genes of both the BALB/c mice and the mixed strains
>with a high rate of West Nile deaths, the researchers isolated a
>specific gene variation that increased the susceptibility to the
>virus, the researchers report. They called the variation the West
>Nile gene.
>
>Dr. Jean-Louis Guenet of Pasteur, a co-author of the study appearing
>this week in The Proceedings of the National Academy of Sciences,
>said the West Nile gene allows the virus to cause disease by
>blocking production of a group of proteins that normally prevent
>viruses from reproducing
>inside a cell.
>
>The exact gene variation has not been found yet in humans, Dr.
>Guenet said. But other researchers said the study was still
>important.
>
>"The possibility of developing a drug is why we are excited about
>this finding," said James M. Meegan, a virology research program
>leader at the National Institute of Allergy and Infectious Diseases
>at the National Institutes of Health.
>
>Dr. Meegan said that his agency was financing research on three
>vaccines for West Nile virus and that one might be ready for human
>trials next year.
>
>...SNIP...
>
>
>
>2) ABSTRACT OF RESEARCH ARTICLE ON WHICH NEWS STORY IS BASED, FROM
>AUG 20, 2002 PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES
>
>Proc. Natl. Acad. Sci. USA, Vol. 99, Issue 17, 11311-11316, August 20, 2002
>Full text on line: www.pnas.org/cgi/doi/10.1073/pnas.172195399
>
>Genetics
>
>A nonsense mutation in the gene encoding 2'-5'-oligoadenylate
>synthetase/L1 isoform is associated with West Nile virus
>susceptibility in laboratory mice
>
>Tomoji Mashimo*, Marianne Lucas, Dominique Simon-Chazottes*,
>Marie-Pascale Frenkiel, Xavier Montagutelli*, Pierre-Emmanuel
>Ceccaldi, Vincent Deubel§, Jean-Louis Guénet*,¶, and Philippe
>Desprès,¶
>
>* Unité de Génétique des Mammifères, Unité des Interactions
>Moléculaires Flavivirus-Hôtes, and Unité de la Rage, Institut
>Pasteur, 75015 Paris, France; and § Unité de Biologie des Infections
>Virales Émergentes, Institut Pasteur, 69007 Lyon, France
>
>Edited by Wolfgang K. Joklik, Duke University Medical Center,
>Durham, NC, and approved June 26, 2002 (received for review April 1,
>2002)
>
>A mouse model has been established to investigate the genetic
>determinism of host susceptibility to West Nile (WN) virus, a member
>of the genus flavivirus and family Flaviviridae. Whereas WN virus
>causes encephalitis and death in most laboratory inbred mouse
>strains after peripheral inoculation, most strains derived from
>recently trapped wild mice are completely resistant. The phenotype
>of resistance/susceptibility is determined by a major locus, Wnv,
>mapping to chromosome 5 within the 0.4-cM-wide interval defined by
>markers D5Mit408 and D5Mit242. We constructed a high resolution
>composite/consensus map of the interval by merging the data from the
>mouse T31 Radiation Hybrid map and those from the homologous region
>of human chromosome 12q, and found the cluster of genes encoding
>2'-5'-oligoadenylate synthetases (2'-5'-OAS) to be the most
>prominent candidate. This cluster encodes a multimember family of
>IFN-inducible proteins that is known to play an important role in
>the established endogenous antiviral pathway. Comparing the cDNA
>sequences of 2'-5'-OAS L1, L2, and L3 isoforms, between susceptible
>and resistant strains, we identified a STOP codon in exon 4 of the
>gene encoding the L1 isoform in susceptible strains that can lead to
>a truncated form with amputation of one domain, whereas all
>resistant mice tested so far have a normal copy of this gene. The
>observation that WN virus sensitivity of susceptible mice was
>completely correlated with the occurrence of a point mutation in
>2'-5'-OAS L1 suggests that this isoform may play a critical role in
>WN pathogenesis.
>
>Corresponding author: guenet@pasteur.fr or pdespres@pasteur.fr.

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