It has become almost common wisdom that the virus that caused the 1918 flu pandemic was an avian strain introduced into the human population shortly before the pandemic erupted. But a new study disputes that hypothesis, arguing instead that genes of the 1918 virus had circulated in mammalian hosts, most likely pigs and humans, for several years before 1918. Multiple gene-swapping events brought them together in a single killer strain, say the researchers; improving surveillance in humans and in swine could alert scientists to such events early in the future.
The origins of the 1918 virus, which is estimated to have killed at least 20 million people, are still controversial. After painstakingly piecing together the genome of the extinct strain, a team led by virologist Jeffery Taubenberger, then at the Armed Forces Institute of Pathology in Washington, D.C., concluded in 2005 that the virus most closely resembled viruses of avian origin; the team suggested it had become transmissible between humans after a couple of key changes (Science, 7 October 2005, p. 28). The study made many headlines, in part because of the fear that the H5N1 avian influenza virus, which so far transmits poorly between humans, could undergo a similarly fateful transformation. But others have questioned Taubenbergers's conclusions.
To study the origins of the three 20th century pandemic flu viruses, Robert Webster of St. Jude Children's Research Hospital in Memphis, Tennessee, and his colleagues took DNA sequences of thousands of flu isolates dating back as far as the 1930s--as well as the 1918 strain--and fed them into models that calculate the most likely evolutionary relationships between them. They report today in the Proceedings of the National Academy of Sciences that genes of the 1918 virus were most likely present in swine or human hosts at least 2 and possibly 15 years before the pandemic began and combined to form the deadly virus during multiple reassortments, presumably rare events in which flu viruses exchange genes. "The data don't really fit with the idea that it was a recent avian introduction," says Gavin Smith of the University of Hong Kong, who carried out the computational analysis.
"I think it's a reasonable conclusion," says Oliver Pybus, an evolutionary biologist at the University of Oxford in the United Kingdom, "although personally, I'd still leave the door open" for an avian origin. Taubenberger, now at the U.S. National Institute of Allergy and Infectious Diseases in Bethesda, Maryland, is not convinced. He points out that relying on sequences from the 1930s and '40s, the early days of influenza science, is tricky, because the viruses ratcheted up mutations as they were grown in animals. He also points out that although veterinarians have recognized flu in horses for centuries, flu in pigs wasn't described until 1918, which seems odd if the virus was present several years earlier. The bottom line, however, is that data are so scant that scientists can never fully know what happened before 1918, Taubenberger says.
The study has a practical upshot, the authors say. In flu surveillance, researchers look primarily for the genes encoding the virus's surface proteins, hemagglutinin and neuraminidase; if they sequence the so-called internal genes as well, they might detect new genes slipping into human virus strains in the run-up to a pandemic, they say. In addition, surveillance in pigs should be expanded, says Webster--although he doubts that anyone will make the money available to do so.