Scientists Discover Clue To How Bird Flu Might Spread In Humans

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Main Category: Bird Flu / Avian Flu
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Article Date: 02 Mar 2007 - 6:00 PDT

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A team of European scientists has discovered a possible clue to how the bird flu virus might spread in humans. Using a 3-D image of a crucial part of the viral protein polymerase they found it sends signals to human host proteins instructing them to carry it into host cells where viral replication then proceeds.

The findings are published in the journal Nature Structural and Molecular Biology.

The 1918 flu pandemic that killed 50 million people worldwide was caused by a mutated strain of bird flu that "learned" how to pass from human to human.

The current deadly bird flu virus H5N1 does not have this ability - the only route to human infection is from infected birds. Many scientists say it is just a matter of time before this strain also "learns" how to cross the bird-human species barrier and begins spreading from human to human.

They say the more human infections that occur, the greater the chances of the virus mutating into a human to human transmissible form.

In order to avert or prepare for such a crisis, scientists all over the world are racing to find out everything they can about how the bird flu virus gets into human host cells and how it replicates once it gets there.

One important area of investigation is the behaviour and structure of viral proteins such as polymerase because it makes copies of the viral genome and controls the production of viral proteins.

For some years now scientists have suspected that particular mutations in this protein will help the virus jump the species barrier from bird to human. Many believe that interfering with polymerase production or targetting weak points on the molecule is a viable route for drug development.

However, getting enough of the protein for experimental purposes is very hard.

The scientists who have produced the first 3-dimensional image of a crucial part of the polymerase viral protein are based at the European Molecular Biology Laboratory (EMBL) in Grenoble and Heidelberg, the Institut de Biologie Structurale (IBS) and the Unit of Virus Host Cell Interactions (UVHCI), both also in Grenoble.

Using this first ever atomic level visualization they found a previously overlooked "signal" that the polymerase molecule switches on when it wants to hitch a ride into the host nucleus.

This signal is "obeyed" by a transporter protein in the human host, importin alpha, which effectively "shuttles" the polymerase into the host nucleus where it can go about its business of replicating viral genome.

Using a sophisticated X-ray machine, the scientists were then able to look at a high-resolution image of the two proteins interacting with each other.

They discovered that protein mutations that were known to play a role in the transmission of bird flu to mammals were inside, or near to the site where the two proteins interacted.

The research team suggests that mutations of polymerase would thus change the efficiency of nuclear transport which in turn affects the ability of the virus to replicate in different species.

Stephen Cusack, head of EMBL at Grenoble, said that "Interfering with polymerase function could provide new ways to treat or prevent flu." He added that further work is being done in this area through the FLUPOL project, a joint effort with other European laboratories that is being funded by the European Commission.

"We will explore both structure and function of this key drug target and try to characterise other mutations implicated in bird-to-human transmission," he added.

"Structure and nuclear import function of the C-terminal domain of influenza virus polymerase PB2 subunit."
Franck Tarendeau, Julien Boudet, Delphine Guilligay, Philippe J Mas, Catherine M Bougault, Sébastien Boulo, Florence Baudin, Rob W H Ruigrok, Nathalie Daigle, Jan Ellenberg, Stephen Cusack, Jean-Pierre Simorre and Darren J Hart.
Nature Structural and Molecular Biology, Published online: 25 February 2007.
doi:10.1038/nsmb1212.

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Written by: Catharine Paddock
Writer: Medical News Today
Copyright: Medical News Today
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