Critical gene a suspect in lethal epidemic
<<< Back to Vaccines
ProMED-mail is a program of the
International Society for Infectious Diseases
Date: Thu 7 Oct 2004
From: ProMED-mail
Source: New York Times, Thu 7 Oct 2004 [edited]
Critical gene a suspect in lethal epidemic
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.
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.
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.
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.
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.
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.
"Thus, a large section of the population would be susceptible to an
outbreak of a 1918-like influenza virus," he and his colleagues conclude.
[byline: Nicholas Wade]
- --
ProMED-mail
[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
.
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.
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. 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."
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]
Zeus Information Service
Alternative Views on Health
www.zeusinfoservice.com
All information, data and material contained, presented or
provided herein is for general information purposes only and
is not to be construed as reflecting the knowledge or opinion
of Zeus Information Service.
Subscribe Free/Unsubscribe: email
[email protected]
Feel free to forward far and wide!
Back to top of Document
