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.
The "Spanish flu" pandemic of 1918 killed over 20 million people worldwide. Above: Two Red Cross nurses tend to a patient at a Red Cross emergency ambulance station in Washington, D.C., during the outbreak.
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 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.
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.
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