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Monday, 30 August 2004

Resurrecting the Dead and the Deadly

James Stevens and Ian A. Wilson
The Scripps Research Institute, 10550 North Torrey Pines Road, La Jolla, CA

Researchers have literally unearthed clues as to why the 1918 influenza pandemic was so deadly. The 1918 influenza pandemic ranks as the largest and most destructive outbreak of an infectious disease, killing 20 to 40 million people worldwide. Using fragments of the flu genome from Alaskan victims preserved by permafrost and army autopsy tissues, James Stevens and Ian Wilson of the Scripps Research Institute in La Jolla, California and their collaborators have assembled genes from the 1918 flu virus.

The Scripps researchers then cloned, expressed and crystallized the viral protein, called hemagglutinin (HA) and utilized SSRL's macromolecular crystallography beam lines to reveal the coils, stalks and heads that make up HA's structure. The intricate structure helps explain why the 1918 flu virus was unusually virulent. HA is the most abundant protein on the virus's surface and as such is the main target for the immune system to try to defend against infection. For the virus, HA is also very important because it binds to human lung cells and enables the virus to get internalized into the cell inside sacs called vesicles. Once inside, HA changes shape to help the viral membrane fuse to the vesicle membrane allowing for infection to proceed. While 1918 HA appeared to be at the base of the evolutionary tree of human viruses, its structural analysis shows that it is actually more closely related to avian (bird) forms.

Two features of the structure particularly stand out in potentially contributing to the extraordinarily high infectivity and mortality rates observed in 1918. The receptor binding site (for the virus to attach to human cells) is narrow and is only a single mutation away from a known swine-avian virus. The mutation makes the binding site slightly larger, which could increase affinity for human cells. The researchers also observed two previously unseen basic patches (histidine rich) which may boost HA infectivity when it fuses to the vesicle membrane in order to escape and replicate itself inside human cells. One of the patches is found only in avian forms of HA, "providing tantalizing evidence of a direct jump of this virus from birds to the human naïve population," said the researchers.