September 2001

From University of Wisconsin-Madison

Slight molecular tweak, and flu virus becomes a killer

MADISON - By incorporating the slightest change in the arrangement of its molecules, the virus responsible for a brief but frightening influenza outbreak in Hong Kong several years ago can quickly morph from a relatively benign virus to a killer.

The discovery of the molecular basis for the extreme virulence of the virus known to scientists as Hong Kong H5N1 influenza A, was reported today, Sept. 7, in Science magazine, the nation's leading scientific journal. Using mice, a team of scientists from the University of Wisconsin-Madison showed that only minor molecular changes are required to turn a virus that, in its benign form, causes only minor respiratory illness to a potentially deadly virus that infects much of the body, including the heart and brain.

"Only a few changes make non-pathogenic viruses highly pathogenic," says Yoshihiro Kawaoka, a virologist at UW-Madison and corresponding author of the Science paper.

The virus responsible for the 1997 Hong Kong outbreak, which infected at least 18 people and killed six of those with known infections, is an avian flu virus and was transmitted to humans, most likely, in one or more of the bustling live poultry markets that dot Hong Kong.

Animals such as fowl and pigs are known reservoirs of influenza virus, and it is known that the major flu outbreaks - including the Asian and Hong Kong flu pandemics - occur when viruses leap from an animal host to humans.

At the time of the outbreak, a surveillance team found the virus in chickens, ducks, quail and geese. To stem the spread of the virus, the Hong Kong government ordered the destruction of all birds in Hong Kong's live poultry markets and an estimated 1.4 million birds were slaughtered.

Kawaoka says two unique things about the 1997 Hong Kong outbreak raise concern among virologists and public health officials: One was direct transmission of the virus from birds to humans, raising the specter that influenza outbreaks in humans could stem more often from live poultry markets which are common in many countries, including the United States in New York and Florida.

The other unique aspect of the outbreak was the extreme virulence of one of two forms of the virus. All human H5N1 isolates proved deadly when chickens were exposed to the virus: "It kills chickens within 36 hours," says Kawaoka, whose research was supported by the National Institute of Allergy and Infectious Diseases. "It causes systemic infection and the virus even grows in the brain."

Whether or not the pathogenic form of the virus was responsible for the six human deaths attributed to the virus is an open question, Kawaoka says. But experiments in mice show that the virulent form of the virus, isolated from human patients who contracted it, can be as deadly to mammals as it is to birds.

As few as two particles of the virus isolated from human victims of the 1997 outbreak were enough to kill a mouse, Kawaoka says. The less virulent form of the virus, isolated from patients who suffered only mild respiratory symptoms, was also less pathogenic in mice.

Flu viruses, like all viruses, depend on the cellular machinery of their hosts to reproduce and spread. The complicated surface landscape of a virus is the key it uses to attach to host cells and co-opt their reproductive capabilities.

The surface proteins of flu viruses change readily to escape detection by the human immune system. The new research suggests, however, that such changes may also trigger changes that can transform the virus from merely sickening to deadly.

In the case of H5N1 influenza A, it seems that only a minor change in the virus was enough to permit it to spread beyond the respiratory system to other vital organs, including the heart and the brain.

Intriguingly, the host seems to play a role in turning the virus into a killer, Kawaoka says. He says a viral protein known as PB2 exhibits a malleability that, apparently, is the key to unleashing the virus and permitting it to spread beyond the respiratory system. The resulting is a single amino acid change that "makes the virus quite different and virulent."

Although the 1997 outbreak of H5N1 influenza A did not appear to spread readily among humans, the persistence of the virus in chickens and other fowl is troubling. In May of this year, a similar H5N1 virus was again detected in chickens from Hong Kong poultry markets and another 1.4 million birds were slaughtered. In June, the poultry markets were reopened and by July, Kawaoka says, the virus was back.

The lead author of the paper appearing in today's Science is Masato Hatta of UW-Madison. Co-authors include Peng Gao and Peter Halfmann, also of UW-Madison.

NOTE TO REPORTERS: Yoshihiro Kawaoka will be traveling to Japan beginning Saturday, Sept. 1. He will be available for interviews the afternoon of Friday, Aug. 31. He can be reached by e-mail anytime. He also be available by phone from Japan Sept. 3-4 after 3:30 p.m. U.S. central time. For help reaching Kawaoka in Japan, contact Terry Devitt, 608- 262-8282, trdevitt@facstaff.wisc.edu Devitt will check voice mail Sept. 3, Labor Day, for messages from reporters who may need to contact Kawaoka.

NOTE TO PHOTO EDITORS: A high-resolution image of Kawaoka is available for downloading at: http://www.news.wisc.edu/newsphotos/kawaoka.html











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