- INFLUENZA A VIRUS, VIRULENCE, 1918 PANDEMIC STRAIN
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- Date: Thu 7 Oct 2004
- From: ProMED-mail
- Source: New York Times, Thu 7 Oct 2004 [edited]
- http://www.nytimes.com/2004/10/07/science/07virus.html
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- Critical Gene A Suspect In Lethal Epidemic
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- By Nicholas Wade
- 10-8-4
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- 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 human history. The gene, one of
8 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 Washington.
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- Drs Kawaoka, Taubenberger, and others have been reinserting
the 1918-type genes into ordinary influenza viruses to see whether 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 haemagglutinin 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 influenza 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 Winnipeg, Canada. 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.
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- 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 influenza viruses
in a Level 3 facility owned by the Department of Agriculture in Athens,
Ga.
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- 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 3-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 made [the virus] so lethal.
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- That makes it necessary to conduct 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 roles, seems
able to trigger the release of cytokines, the signaling agents with which
the immune system gears itself up for massive attack against an infectious
agent. 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.
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- 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
influenza virus do not.
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- "Thus, a large section of the population would be
susceptible to an outbreak of a 1918-like influenza virus," he and
his colleagues conclude.
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- -- ProMED-mail
- promed@promedmail.org
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- The reference for the paper cited above is as follows:
Darwyn Kobasa, et al. Enhanced virulence of influenza A viruses with the
haemagglutinin of the 1918 pandemic virus. Nature 2004; 431: 703-7 (7 Oct
http://www.nature.com/cgitaf/DynaPage.taf?file=/
nature/journal/v431/n7009/abs/nature02951_fs.html . The 19 authors are
from the Department of Pathobiological Sciences, University of Wisconsin,
Madison, Wisconsin, the Special Pathogens Program, National Microbiology
Laboratory, Health Canada and Department of Medical Microbiology, University
of Manitoba, Winnipeg, Manitoba, Canada, and 7 research institutions in
Japan.
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- The introduction to the paper states that: "The
'Spanish' influenza pandemic of 1918-19 was the most devastating outbreak
of infectious disease in recorded history. At least 20 million people died
from their illness, which was characterized by an unusually severe and
rapid clinical course. The complete sequencing of several genes of the
1918 influenza virus has made it possible to study the functions of the
proteins encoded by these genes in viruses generated by reverse genetics,
a technique that permits the generation of infectious viruses entirely
from cloned complementary DNA.
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- Thus, to identify properties of the 1918 pandemic influenza
A strain that might be related to its extraordinary virulence, viruses
were produced containing the viral haemagglutinin (HA) and neuraminidase
(NA) genes of the 1918 strain. The HA of this strain supports the pathogenicity
of a mouse-adapted virus in this animal. Here we demonstrate that the HA
of the 1918 virus confers enhanced pathogenicity in mice to recent human
viruses that are otherwise non-pathogenic in this host. Moreover, these
highly virulent recombinant viruses expressing the 1918 viral HA could
infect the entire lung and induce high levels of macrophage-derived chemokines
and cytokines, which resulted in infiltration of inflammatory cells and
severe haemorrhage, hallmarks of the illness produced during the original
pandemic."
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- This is a significant piece of research, suggesting that
the virulence of the 1918 pandemic influenza virus may have been a property
of its HA gene. However, it does not identify the specific feature of this
HA molecule that promotes the enhanced inflammatory response (in mice).
- Mod.CP
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- Patricia A. Doyle, PhD
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