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January 18, 2007

Study uncovers a lethal secret of 1918 influenza virus

In a study of non-human primates infected with the influenza virus that killed 50 million people in 1918, an international team of scientists has found a critical clue to how the virus killed so quickly and efficiently. The group was led by University of Wisconsin-Madison virologist Yoshihiro Kawaoka, and includes Michael Katze, professor of microbiology at the UW, and his colleagues here.


Writing in the Jan. 18 issue of the journal Nature, the team reports how the virus — modern history’s most savage influenza strain — unleashed an immune response that destroyed the lungs in a matter of days and lead to death.

The finding is important because it provides insight into how the virus that swept the world in the closing days of World War I was so efficiently deadly, claiming as many of its victims people in the prime of life. The work suggests that it may be possible in future outbreaks of highly pathogenic flu to stem the tide of death through early intervention, and it proves that the virus was different from all of the other flu viruses currently studied.

The new study, conducted at the Public Health Agency of Canada’s National Microbiology Laboratory in Winnipeg, Manitoba, utilized the 1918 flu virus, which has been reconstructed by researchers using genes obtained from the tissues of victims of the great pandemic in a reverse genetics process that enables scientists to make fully functioning viruses. The research gives clues into the longstanding mystery of why the 1918 flu was so deadly, and it will help scientists better understand all influenza viruses and their ability to cause pandemics.

By infecting monkeys with the virus, the team was able to show that the 1918 virus prompted a deadly respiratory infection that echoed historical accounts of how the disease claimed its victims. Researchers found that the immune response prompted by the virus seems to derail the body’s typical reaction to viral infection and instead unleashes an attack by the immune system on the lungs. As immune cells attack the respiratory system, the lungs fill with fluid and victims, in essence, drown.

The mechanisms that contribute to the lethality of the virus were uncovered by UW researchers using functional genomics, a technique in which they analyze the gene functions and interactions. Learning more about the virulence mechanisms of the 1918 flu virus may help researchers understand how to keep the virus from causing such a severe immune response.

“This study in macaques, combined with our earlier research showing the host response in mice infected with the 1918 flu, suggests that the host immune response is out of control in animals infected with the virus,” said Katze, the UW scientist who led the functional genomics portion of the new study and led the previous mouse-based study. “Our analysis revealed potential mechanisms of virulence, which we hope will help us develop novel antiviral strategies to both outwit the virus and moderate the host immune response.”

The same excessive immune reaction is characteristic of the deadly complications of H5N1 avian influenza, the strain of bird flu present in Asia and which has claimed nearly 150 human lives but has not yet shown a capacity to spread easily among people.

The new study was conducted in a high-level biosafety laboratory (BSL 4) at the Public Health Agency of Canada’s National Microbiology Laboratory in Winnipeg, Manitoba.