Researchers Chart Flu's Global Journey
Strains Arise in Asia, Die in S. America

By David Brown
Washington Post Staff Writer
Thursday, April 17, 2008

New strains of seasonal influenza virus all arise in East or Southeast Asia and take a largely predictable route around the world before dying out for good in South America, the global glue-trap for the pathogen.

That is the conclusion reported yesterday by a large team of researchers who analyzed the genetic ancestry of about 13,000 virus samples collected from six continents over a five-year period to answer long-standing questions about the flu's life cycle.

The findings help explain the biological mechanisms that underlie two long-held observations about flu: New strains tend to appear first somewhere near China, and Australia's flu season is a preview of what will happen in North America six months later. They also help explain why one winter's flu is always at least a little bit different from the previous winter's, even though the virus disappears over the summer.

The researchers hope the insights may help virologists better predict what strains of virus to include in annual flu shots, which must be manufactured anew each year. Although usually accurate, those predictions occasionally miss, as they did this year when the North American vaccine provided little protection against the strain causing most illness.

"If we want to know what will be happening in a year, we really need to pay attention to what is happening in East and Southeast Asia," said Derek J. Smith, a biologist at the University of Cambridge in England.

Previously, scientists were uncertain how and where influenza virus evolves between epidemics, which occur in winter in temperate climates.

One theory was that flu virus survives largely unnoticed each summer, with the first cases each winter caused by leftover -- and slightly changed -- strains. Another theory held that the virus dies out completely in temperate climates each summer but flourishes year-round in tropical zones, which are the nurseries for new variants. A third theory was that all new strains come from China, largely because of its population density.

The researchers analyzed virus samples collected from 2002 to 2007 and compared the molecular fingerprints of the gene for hemagglutinin, the protein that gives flu strains their distinct identities.

They found that each year's dominant strain in Europe, the Americas or other regions was traceable to ancestors first seen in a large region of East and Southeast Asia (an area bigger than China alone). It was never directly descended from a strain seen in temperate zones the previous year. In fact, the evidence strongly suggested that flu virus goes extinct each summer in temperate climates -- there is none left to smolder and evolve.

What the researchers now believe happens is that the world is reseeded each year by new, slightly different variants. "The strains are coming out [of Asia] fully formed," Colin A. Russell, one of the researchers, said in a telephone news conference.

The route the new strains then take seems to reflect both proximity to East Asia and the amount of travel between regions. The first stops are Australia and the Pacific islands known as Oceania, which the virus reaches about three months after it arises in Asia. Three to six months later it crops up in Western Asia, Europe and then North America. The last stop is South America.

"It is a surprise to everyone that South America is the end of this seeding hierarchy," Russell said.

But why is East-Southeast Asia always the starting point? The researchers believe it's because of the unusual concentration of different climates there. The region has both tropical environments, where flu flourishes during the rainy season, and temperate zones. There are places that are relatively close -- Russell cited Bangkok and Kuala Lumpur, Malaysia, 700 miles apart -- that have totally different flu seasons.

This effectively allows new strains to be passed around the region like a baton in a relay race, even though in each climate zone the virus completely dies out once a year.

The reason new variants don't cause epidemics if they are carried back to East Asia from elsewhere is because people already have immunity to them. They're old news. At least that's the theory.

The Science paper complemented one published this week in the competing journal Nature.

Edward C. Holmes, a biologist at Pennsylvania State University, and his collaborators studied about 1,300 influenza virus samples gathered from New York state in the Northern Hemisphere and New Zealand in the Southern Hemisphere over 12 years. They examined the genetic fingerprints of all eight gene segments of the flu virus, not just hemagglutinin.

They found that one region's year-to-year virus strains were not directly descended from each other but instead appeared to come from a "reservoir" population somewhere, Holmes said. He added that the results were "completely compatible" with the Cambridge group's findings.

The Penn State group also found that new, successful flu variants weren't just ones that had different hemagglutinin proteins to which people were not likely to be immune. Many also showed evidence of having traded genes with other flu viruses, with some of these "reassorted" strains more successful than those that evolved by small steps.

Neither of these papers address the origin of flu viruses that cause severe global pandemics such as the one that killed at least 50 million people in 1918 and 1919. Those arise from the mixing of human flu viruses and ones carried by birds or pigs -- a much rarer event than the predictable evolution of human viruses year to year.

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