Critical Gene a Suspect in Lethal Epidemic
October 7, 2004
By NICHOLAS WADE
By recreating the influenza virus that killed up to 50
million people in 1918-19, researchers may have identified
the gene that turned it into one of the most lethal in
The gene, one of eight in the virus, seems to have an
unexpected capacity for sending the body's immune system
into overdrive, causing inflammation, hemorrhage and death,
the scientists report today in the journal Nature.
The research team, led by Dr. Yoshihiro Kawaoka of the
University of Wisconsin, has been trying to determine just
why the 1918 virus was so lethal and how defenses could be
devised if a similar virus appeared in the future. Although
the virus has long since perished, Dr. Kawaoka and his
colleagues were able to recreate it because the composition
of its genes had been reconstructed from the preserved
tissue of victims. The genes have been reconstituted over
the last few years by Dr. Jeffery K. Taubenberger and
colleagues at the Armed Forces Institute of Pathology in
Dr. Kawaoka, Dr. Taubenberger and others have been
reinserting the 1918-type genes into ordinary flu viruses
to see if they can pinpoint which of the genes made the
virus so lethal and how it did so. In the latest of these
experiments, which Dr. Kawaoka reports today, a gene called
the hemagglutinin or HA gene seems to be largely
responsible for the dire effects of Spanish flu, as the
1918 epidemic is also known.
Recreating such a dangerous organism is not an experiment
to be undertaken lightly. Dr. Kawaoka's approach required
replacing the HA and another gene in a mild flu virus with
the Spanish flu versions and infecting mice with the novel
agent. Because of the obvious hazards, he at first
conducted the work in the most secure type of biological
laboratory, designated Biosafety Level 4, one of which was
available at the National Microbiological Laboratory in
He said that after satisfying himself that the souped-up
virus was susceptible to an antiviral agent known as
Tamiflu, he transferred the research to a Biosafety Level 3
laboratory at the University of Wisconsin.
Dr. R. Timothy Mulcahy, chairman of the university's
biosecurity task force, said that the chances of escape
from the Biosafety Level 3 facility were minimal and that
Dr. Kawaoka had been "extremely prudent" in starting out at
the higher level. "If there were an escape there would be
treatments," Dr. Mulcahy said. He noted that another group
of researchers had already worked with similar engineered
flu viruses in a Level 3 facility owned by the Department
of Agriculture in Athens, Ga.
The HA gene studied by Dr. Kawaoka's team is well known to
flu experts because it changes from year to year. Since the
protein made by the gene is the one singled out for attack
by the immune system, the body's defenses are caught off
guard each year as flu virus arrives with a novel version
of the protein to which the body has no prior immunity.
The HA protein's role is to latch onto the surface of human
cells and then help the virus merge into the cell's outer
membrane. Researchers recently worked out the exact
three-dimensional structure of the Spanish flu version of
the HA protein, but could see no other function that it was
designed to serve. The same is true of the other Spanish
flu genes recovered by Dr. Taubenberger. In the current
state of knowledge, the genes betray no clear hint of what
makes them so lethal.
That makes necessary experiments like Dr. Kawaoka's, in
which researchers physically reconstruct the virus and try
to understand how it works. What he has now found is that
the Spanish flu version of the HA gene, in addition to its
break-in and enter role, seems able to trigger the release
of cytokines, the signaling agents with which the immune
system gears itself up for massive attack against an
Uncontrolled overdrive can make the immune system kill the
body in order to save it, through excessive inflammation.
The virus carrying the Spanish flu version of the HA gene
produced high levels of cytokines in mice, Dr. Kawaoka
says, and this is probably what led to the inflammation and
lung damage that killed them.
Dr. Adolfo Garcia-Sastre, a flu expert at the Mount Sinai
School of Medicine who has constructed a similar virus,
said the HA gene might be causing extra virulence simply by
helping the virus replicate better, not because of any
special effect on cytokine production. But either way, the
finding helped focus attention on the gene's role, he said.
Survivors of the 1918 epidemic have high levels of antibody
to the engineered virus, Dr. Kawaoka reports, but people
infected recently with a similar class of flu virus do not.
"Thus, a large section of the population would be
susceptible to an outbreak of a 1918-like influenza virus,"
he and his colleagues conclude.