The following article from Science Magazine discusses recent research findings identifying the mutations that need to take place in order for an avian influenza virus to become readily transmissible among humans. One can only hope that as the scientific understanding of the virology becomes more sophisticated, the prospects for effective vaccines and cures will improve. On the other hand, it is also fair to surmise that the same virological sophistication will make it easier to create, in the lab, designer viruses for use as bioterrorism weapons.
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HIV is lethal but not all that infectious; the common cold spreads easily
but is fairly innocuous. The Spanish flu virus of 1918-1919 had the worst
qualities of both, which is why it killed more people than World War I did.
But although virologists have learned a lot about the combination of genes
that made the virus so deadly, they could only speculate why it spread so
easily.
No longer. A study published by Science this week [see Abstract below]
confirms what many had suspected: A small change in the virus's
hemagglutinin (HA) -- a glycoprotein sitting on its surface by the hundreds
- -- makes the 1918 virus more "avian" and unable to transmit between
ferrets, even though it still sickened them. Those same changes in reverse
may be what started the 1918 catastrophe -- and what could kick off the
next one as well.
"This is world news," says flu virologist Ron Fouchier of Erasmus Medical
Center in Rotterdam, the Netherlands. "This answers the million-dollar
question of how an avian virus can become transmissible between mammals."
Still, exactly how the change in HA -- which required just 2 point
mutations -- renders the virus impotent remains unclear, Fouchier says. Nor
does it answer an even more urgent question: Could a similar set of
mutations turn the bird flu virus H5N1, now devastating poultry in many
countries, from an avian scourge into a human nightmare?
The HA in human flu viruses, such as the annual strains now sickening
millions in the Northern Hemisphere, preferentially binds to a receptor on
host cells that features a sialic acid bound to galactose through a linkage
called alpha-2,6. This receptor predominates in both human and ferret
airways. By contrast, avian viruses such as H5N1 have an HA with a slightly
different shape that prefers to bind to a sialic acid linked to galactose
through an alpha-2,3 link; these are in the majority in bird guts.
Based on that knowledge, researchers had suggested that the 1918 virus
arose when an avian virus acquired mutations that gave it its predilection
for alpha-2,6, thus becoming more "human" in nature. If so, reversing those
mutations should be able to "avianize" the 1918 virus and make it unable to
transmit among humans, says Terence Tumpey of the U.S. Centers for Disease
Control and Prevention (CDC) in Atlanta, Georgia, the main author of the
new study.
So Tumpey, with colleagues at CDC and Mount Sinai School of Medicine in New
York City, took the 1918 virus -- which was resurrected over the past
decade and is now the subject of intense study (Science, 7 Oct 2005, p. 28)
- -- and made a few point mutations. One gave it an affinity for both the
alpha-2,3 and alpha-2,6 receptors. One more switched its preference
completely toward alpha-2,3.
When the researchers inoculated ferrets (the best animal model for human
flu) intranasally with high doses of these 2 viruses, as well as the
original 1918 strain, all 3 caused severe disease. But the ferrets to watch
were those living in the cages next to the sick ones.
With the original 1918 strain, they, too, became infected and got sick.
With the strain that had a mutation that made it bind to both a-2,3 and
a-2,6 receptors, transmission was inefficient; 2 out of 3 ferrets in
adjoining cages developed antibodies, although neither became really ill.
In the strain that bound to a-2,3 only, there was no transmission whatsoever.
The study provides the 1st direct evidence that receptor preference is key
to transmission, says virologist Mikhail Matrosovich of the National
Institute for Medical Research in London. But why a few point mutations can
have such a dramatic effect is less clear, he says. Although a-2,6
receptors predominate in ferrets, they also have a-2,3 receptors, as do
humans; that's why the avianized virus was able to infect them. So why
couldn't this strain make the jump to the next cage? One clue lies in 2006
studies that showed that human cells with a-2,3 receptors occur primarily
deep in the lungs, from where the virus may not so easily escape. a-2,6
receptors, in contrast, were found primarily in the upper respiratory
tract. Another hint is that the ferrets infected with the avianized virus
didn't sneeze, Tumpey says; it's not hard to see why that would reduce
transmission in ferrets.
Several groups, meanwhile, are trying to find out if H5N1, too, could
become a humanized virus through a few mutations in HA. Mutations in other
genes are probably necessary as well, says Yoshihiro Kawaoka of the
University of Wisconsin, Madison, and the University of Tokyo, and if
humankind is lucky, researchers may discover that the combination of
changes needed is unlikely to occur in nature. But in any case, knowing in
advance what it takes would give scientists something to be on the lookout
for in dead birds and human patients, Fouchier says, and ring the alarm
bell if necessary.
[Byline: Martin Enserink]
[Byline: Martin Enserink]
- --
Pablo Nart
<pablo.nart@terra.es>
[The following is the Abstract of the paper referred to in Martin
Enserink's Science News article. Updated information and services,
including high-resolution figures, can be found at:
<http://www.sciencemag.org/cgi/content/full/315/5812/655>
"Title: A Two-Amino Acid Change in the Hemagglutinin of the 1918 Influenza
Virus Abolishes Transmission
Authors: Terrence M. Tumpey, Taronna R. Maines, Neal Van Hoeven, Laurel
Glaser, Alicia Solórzano, Claudia Pappas,,2 Nancy J. Cox, David E. Swayne,
Peter Palese, Jacqueline M. Katz, Adolfo García-Sastre.
Abstract: The 1918 influenza pandemic was a catastrophic series of virus
outbreaks that spread across the globe. Here, we show that only a modest
change in the 1918 influenza hemagglutinin receptor binding site alters the
transmissibility of this pandemic virus. Two amino acid mutations that
cause a switch in receptor binding preference from the human {alpha}-2,6 to
the avian {alpha}-2,3 sialic acid resulted in a virus incapable of
respiratory droplet transmission between ferrets but that maintained its
lethality and replication efficiency in the upper respiratory tract.
Furthermore, poor transmission of a 1918 virus with dual {alpha}-2,6 and
{alpha}-2,3 specificity suggests that a predominant human {alpha}-2,6
sialic acid binding preference is essential for optimal transmission of
this pandemic virus. These findings confirm an essential role of
hemagglutinin receptor specificity for the transmission of influenza
viruses among mammals."
These experiments are a direct consequence of the development of reverse
genetic techniques whereby specific mutations can be introduced into the
genome of influenza viruses. The experiments described in this paper define
minimal genetic changes in the haemagglutinin protein of influenza virus
which affect its transmissibility. This knowledge may facilitate prediction
of the imminence of evolution of a human pandemic virus. - Mod.CP] |
