Disastrous 1918 Flu Linked to Birds, Study Says

Stefan Lovgren
for National Geographic News
February 5, 2004

Solving an 86-year-old medical mystery, British scientists have determined the structure of the so-called "Spanish flu" virus that jumped from birds to humans in 1918, killing more than 20 million people worldwide. In two separate studies, researchers from the Medical Research Council in London showed that the virus likely derived from an avian virus and retained some key characteristics of its avian precursor that caught the human immune system off-guard.

Although the discovery will probably not have an immediate impact on the current outbreak of chicken flu in Asia, the work will help scientists better understand flu viruses and their transmission from birds to humans.

The new evidence suggests that "receptor binding," the initial event in virus infection in which a foreign virus mixes with human proteins, is perhaps more important than the virulence of the virus in determining risk of transmission.

"This paper is important because of the knowledge it brings about how these viruses, which originate in birds, can jump to humans," Sir John Skehel, the Medical Research Council's lead scientist on the project, said in a prepared statement. "This allows us to track and monitor the changes in the virus for public health purposes, even though it does not allow us to predict or prevent future forms of flu."

The research is published in tomorrow's issue of the journal Science.

High Mortality Rates

The influenza pandemic in 1918 was named "Spanish flu" because it was first widely reported in Spanish newspapers. News reports of the outbreak were suppressed by wartime censorship in many countries fighting in World War I.

The pandemic was exceptional in both breadth and depth. Unlike most subsequent influenza strains, which first appeared in Asia, the initial wave of the Spanish flu seemingly arose in the United States. In September through November of 1918, it killed more than 10,000 people per week in some U.S. cities.

The pandemic swept not only North America and Europe, but also spread as far as the Alaskan wilderness and remote Pacific islands. The disease was exceptionally severe, with mortality rates of 2.5 percent among those infected, compared to less than 0.1 percent in other influenza epidemics.

Studying what made the Spanish flu so lethal is important because influenza viruses continually evolve. An understanding of the genetic makeup of the most virulent influenza strain ever seen could help health officials manage possible pandemics in the future.

For their new study, the British scientists sequenced sections of the 1918 influenza virus's genome, using samples from flu victims preserved in the Alaskan permafrost.

The first step in infection by flu viruses is their attachment to the cells in which they will replicate themselves. Attachment involves spike-like molecules called hemagglutinins (HA) that project from the viruses and bind to particular receptors on the surface of cells in the body.

Avian Origins

Using a technique known as x-ray crystallography, one group of scientists determined the three-dimensional structure of the 1918 virus's HA protein, as well as the structures of two HA proteins from similar subtypes of the virus. A second group of scientists determined the structure of the precursor protein that becomes HA.

The results reveal that the 1918 viral HA has structural features previously seen primarily in avian influenza viruses. In particular, the receptor's binding site contains the amino acids of the avian virus but positions them in a way that enables them to interact with human proteins, allowing the virus to be transmitted in the human population.

Bird viruses usually don't infect humans because human and bird virus hemagglutinins interact with different cell receptors. As the study shows, for bird viruses to infect people, their hemagglutinins must change so that they can attach to the human receptors in the cell. The structure of the 1918 HA changed to make it capable of attaching to human cells, thus allowing human-to-human transmission.

In contrast, in the outbreak of chicken influenza in Hong Kong in 1997, the virus was extremely virulent, but was not able to bind and was therefore unable to spread.

Some scientists believe wild waterfowl are the natural reservoir for the influenza virus. Since pigs can be infected with both avian and human strains, they are also thought to be an intermediary in the transmission process.

The Current Outbreak

Meanwhile, the current outbreak of bird flu in Asia shows little sign of abating. On Wednesday, two children died of bird flu, raising the death toll to 15. Health officials say that safely destroying infected birds is the best way to contain the disease. Mass slaughter and import bans have ravaged Asia's poultry industry. More than 50 million birds, mostly chickens, have been killed.

But only Vietnam and Thailand have seen human deaths. Most human cases have been traced to contact with sick birds, and even though human-to-human transmission has not been ruled out in the case of one Vietnamese family, officials say there is no sign of a new strain that will infect many people.

However, experts say the wide range of the outbreak boosts chances the virus could mix with a human flu virus and create a hybrid that may develop into a global menace.

The British study of the 1918 flu is unlikely to help scientists gain a better understanding of the current flu.

"[Our study] tells us more about the transmission of infections from birds to humans," said Skehel. "However, it will not have an immediate impact on the situation currently unfolding in the Far East with the chicken flu known as H5, since, from our previous work, we know that the 1918 and the H5 hemagglutinins are quite different."