Gene implicated in deadly influenza

In 1997, a strain of influenza virus jumped from birds to people in Hong Kong. It killed 6 of the 18 people it infected, a proportion that shocked scientists and public health officials worldwide (SN: 12/13/97, p. 372: https://www.sciencenews.org/sn_arc97/12_13_97/fob1.htm).

Although the flu didn’t spread from person to person, Chinese officials exercised extreme caution–ordering the slaughter of 1.4 million chickens and other fowl suspected of carrying the strain.

Scientists have since been deciphering parts of the virus strain’s genetic makeup. The most recent findings pin some of the blame for its virulence on a mutation in a gene encoding the enzyme called PB2, which is crucial to the replication of the virus’ genetic material.

Flu viruses are compact organisms with only a handful of genes. Researchers report in the Sept. 7 Science that a mutant version of PB2 helps the 1997 strain spread efficiently from cell to cell and invade internal organs, such as the brain and heart.

The strain appeared in Hong Kong in two forms: mild and lethal. By swapping PB2-encoding genes between the two forms, the researchers were able to convert the mild form to virulent in mice, says study coauthor Yoshihiro Kawaoka, a virologist at the University of Wisconsin-Madison and the University of Tokyo.

To pinpoint the source of the increased virulence, Kawaoka and his colleagues created new versions of the mild-flu PB2 enzyme by substituting segments of the gene with segments from the virulent form. This process, a type of reverse genetics, revealed a single mutation that rendered the virus virulent.

In most cases, viruses with the new versions of PB2 genes caused only mild flu in the mice. But viruses with one version caused organ failure and, within 5 days, killed all the mice receiving them.

Before 1997, bird flu had never been documented to make people ill directly. “We think this single mutation made the avian influenza virus grow better in mammalian species,” Kawaoka says. “The outcome seems to be efficient viral replication.”

The study “is a technological tour de force,” says John R. La Montagne, deputy director of the National Institute of Allergy and Infectious Diseases in Bethesda, Md., which provided some funds for the work. “The ability to manipulate the flu through reverse genetics has improved our understanding of how this virus spreads.”

This approach has already led to new medications to treat flu, La Montagne says.

However, immunologist Constantin A. Bona of Mount Sinai School of Medicine in New York cautions that flu in mice doesn’t consistently model the disease in people. Also, he says, the PB2 enzyme variant isn’t the only mutation implicated in the 1997 bird flu.

Kawaoka acknowledges that mutations in other genes probably play a role. For example, he says, the virulence of the 1997 flu is no doubt also linked to mutations in the gene encoding hemagglutinin, a surface protein on the flu virus.

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