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Shape of 1918 Flu Protein Provides Clues to Global Pandemic

By Nancy Touchette

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Infectious Diseases

Canadian medical staff await arrival of patients during the Spanish Flu epidemic.
Health officials monitoring the recent outbreak of “bird flu” in Asia have a chilling reminder of what can happen when strains of avian influenza cross over to humans: The influenza pandemic of 1918—the most deadly outbreak of infectious disease ever—killed 40 to 50 million people throughout the world, according to the World Health Organization.

For more than 85 years, biologists have been mystified by what made the “Spanish Flu” virus so lethal.

Now, researchers have reconstructed a key protein from the 1918 virus. They see in its structure clues to how the virus jumped from birds to humans. The protein from the 1918 virus has a sequence that is similar to flu viruses found in birds, which are usually inefficient in infecting human cells. The protein, called hemagglutinin, adopts a shape that allows it to readily latch on to human cells.

The new studies are not likely to help public health officials predict the course of the current avian influenza outbreak, which is caused by a different strain of virus. However, they may help researchers better understand how such viruses adapt to new species and may suggest what changes to look for as the virus mutates.

Because the avian influenza virus can mutate rapidly, health officials are concerned that mutations could result in an altered form of the protein that might make it able to latch on to human cells.

If this happens, the virus could rapidly spread among people. The new research illustrates how changes in this important protein could signal such a switch.

Structure of the 1918 hemagglutinin protein highlights the receptor binding site (blue) and the membrane fusion domain (magenta).
Viral Clues from Frozen Flu Victims

When the 1918 pandemic struck, doctors didn’t know that it was caused by a virus. But in 1999, U.S. Army researchers isolated viral fragments from tissues from flu victims frozen in the Alaska permafrost and from preserved laboratory specimens. From these fragments, they pieced together the sequence of the viral genes. Two groups of researchers then used those viral sequences to produce the protein.

“We wanted to know why the 1918 virus was so devastating,” says Ian A. Wilson, of the Scripps Research Institute in La Jolla, California, who led one of the research teams. “We focused on the hemagglutinin protein because it is required for the virus to bind to and enter cells.”

The protein covers the surface of the influenza virus and acts as a sort of spike that first attaches to the host cell. The protein also helps the virus membrane fuse with the cell membrane, so that the virus can enter the cell being attacked.

The two teams of researchers focused on different aspects of how the protein helps the virus get into cells. One team—a collaboration between John J. Skehel of the Medical Research Council National Institute for Medical Research in London and Don C. Wiley, now deceased, who worked at Harvard University in Cambridge, Massachusetts—focused on how the protein attaches to host cells. Wilson’s team at Scripps focused on how the protein helps the membranes fuse together. The two papers appear together in Science.

“You can think of this protein as a live missile,” says Ya Ha, now of Yale University in New Haven, Connecticut, a former member of Wiley’s lab. “It has a targeting device and it has an explosive.”

Making the Jump from Birds to Humans

Skehel’s team looked at the structure of the protein from the 1918 virus, known as the H1 form of hemagglutinin. They also examined the structure of similar forms of the protein attached to receptors, or attachment sites, from either bird or human cells.

What perplexed researchers studying the 1918 flu epidemic was the presence of mostly avian-like sequences in the binding region of the H1 protein. The sequence suggested that the virus would only be able to attach to avian cells and did not explain why it spread so rapidly among humans.

But when Skehel and his team looked at the three-dimensional structure, they saw that the H1 protein can adopt a different shape that allows it to attach to both bird and human cells.

“The 1918 virus has a lot of features of avian viruses,” says Skehel. “But the shape of its binding site allows it to bind to human cells. When that happens, there shouldn’t be anything stopping it from infecting human cells.”

Skehel speculates that once the virus was able to get into human cells it could have then mutated to more virulent forms that contributed to the widespread human infection.

The Scripps researchers focused on that part of the H1 protein that helps the virus membrane fuse to the host membrane. They noticed an unusual structure in the region of the protein that helps the membranes fuse together. Wilson speculates that the unusual structure may have made fusion more likely.

“Now that we know the structure of the protein, we can start making changes in the sequence of the virus and see how that affects virulence,” says Wilson . “From the structure, we have some new theories. The key now is to do the experiments that will tell us how these viruses infect human cells.”

Influenza Strains and Epidemics

All known flu epidemics in humans have come from the type A influenza virus, which originates in birds. Birds harbor 15 subtypes of the type A virus, but only 6 subtypes are known to have infected humans.

Each strain of the virus contains a different form of the hemagglutinin protein and is named for that protein. For example, the 1918 virus contains the H1 form and is designated as an H1 strain. The current flu outbreak in Asia is caused by an H5 influenza strain, which has the H5 hemagglutinin protein. It is known as the H5N1 strain.

Three of these subtypes—H1, H2, and H3—have adapted to humans, causing three pandemics over the past century, including the 1918 pandemic, also known as the “Spanish flu.”

Three other influenza subtypes, called H5, H7, and H9 have caused small outbreaks when the virus was transmitted directly from birds to humans. But these subtypes have not been transmitted from human to human and have not caused any major epidemics—yet.

The toll from the current outbreak of bird flu in Asia is rising. So far, at least 20 people in Vietnam and Thailand have been hospitalized and 16 people have died. Doctors believe that all the victims contracted the virus directly from birds. They are monitoring the epidemic closely for signs of human-to-human transmission.

For more information and influenza updates visit the World Health Organization.

Stevens, J. et al. Structure of the uncleaved human H1 hemagglutinin from the extinct 1918 influenza virus. Published online in Science, February 5, 2004.
Gamblin, S.J. et al. The structure and receptor-binding properties of the 1918 influenza hemagglutinin. Published online in Science, February 5, 2004.

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