MADISON - Using a gene resurrected from the virus that caused the 1918 Spanish influenza pandemic, recorded history's most lethal outbreak of infectious disease, scientists have found that a single gene may have been responsible for the devastating virulence of the virus.
Writing Oct. 7 in the journal Nature, virologist Yoshihiro Kawaoka of the University of Wisconsin-Madison and the University of Tokyo, describes experiments in which engineered viruses were made more potent by the addition of a single gene. The work is evidence that a slight genetic tweak is all that is required to transform mild strains of the flu virus into forms far more pathogenic and, possibly, more transmissible.
The results of the new work promise to help scientists understand why the 1918 pandemic, a worldwide outbreak of influenza that killed 20 million people, spread so quickly and killed so efficiently, says Kawaoka, who has studied influenza viruses for 20 years. The finding also lends insight into the ease with which animal forms of the virus, particularly avian influenza, can shift hosts with potentially catastrophic results.
"Replacing only one gene is sufficient to make the virus more pathogenic," says Kawaoka, a professor of pathobiological sciences at the UW-Madison School of Veterinary Medicine. In the Nature paper, Kawaoka and his colleagues describe how a Spanish flu gene that codes for a key protein changed a relatively benign strain of flu virus from a nuisance to a highly virulent form.
In the late 1990s, scientists were able to extract a handful of genes from the 1918 virus by looking in the preserved lung tissue of some of the pandemic's victims. Subsequently, the genes were sequenced, including two critical genes that make hemagglutinin and neuraminidase, the protein keys that help the virus enter and infect cells.
Using a comparatively mild form of influenza A virus as a template, Kawaoka's team added the two 1918 genes that code for hemagglutinin and neuraminidase and infected mice with the engineered viruses.
"Here we demonstrate that the [hemagglutinin] of the 1918 virus confers enhanced pathogenicity in mice to recent human viruses that are otherwise non-pathogenic in this host," Kawaoka and his colleagues write in the Nature report. Moreover, the viruses with the 1918 hemagglutinin gene caused symptoms in the mice - infection of the entire lung, inflammation and severe hemorrhaging - eerily similar to those exhibited by human victims of the 1918 pandemic.
Scientists and historians have long speculated about why the 1918 Spanish flu virus was so virulent. Theories range from lack of modern medical care and antibiotics, which had not yet been developed, to the already weakened state of many victims due to war and the tumultuous social conditions of the time.
"There also were people who thought the virus was different in terms of its virulence," Kawaoka says. The results of the new study tend to support the idea that the virus was inherently more dangerous.
Another important result of the new study is that it supports the idea that the 1918 Spanish flu virus was avian in origin, but already adapted to proliferate in humans. That insight is important as scientists and public health officials view birds as a primary reservoir of influenza A virus, strains of which can sometimes jump species to infect other animals, including humans.
According to Kawaoka, it's known that avian strains of the virus have slightly different receptors - key proteins on the surface of the virus that act like a key to unlock and infect host cells - from those on flu viruses that infect humans.
"That restricts transmission from avian species (to humans) to some extent, but not completely," Kawaoka notes.
The receptors on the virus with the gene from the 1918 virus, Kawaoka says, readily recognized their complements on human cells. "That tells you that there was a change in receptor recognition after introduction from avian species to humans. It recognized the human receptor even though it came from an avian species. That's why it transmitted so efficiently among humans."
A third and intriguing finding of the study is that blood from the now very elderly survivors of the 1918 pandemic had high antibody titers to the engineered virus, Kawaoka says.
"People who were infected with this virus in 1918 still have high antibodies, even after 80 years," he says.
That scientifically interesting finding, Kawaoka explains, suggests that another outbreak of flu like the 1918 pandemic would spare many very old people who had had a brush with the virus more than 80 years ago. The irony in that, according to Kawaoka, is that influenza often extracts its heaviest toll on the elderly.
© 2004 The Board of Regents of the University of Wisconsin System.
Kobasa D, Takada A, Shinya K, Hatta M, Halfmann P, Theriault S, Suzuki H, Nishimura H, Mitamura K, Sugaya N, Usui T, Murata T, Maeda Y, Watanabe S, Suresh M, Suzuki T, Suzuki Y, Feldmann H, Kawaoka Y.
Enhanced virulence of influenza A viruses with the haemagglutinin of the 1918 pandemic virus.
Nature. 2004 Oct 7;431(7009):703-707.
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