Colorized transmission electron micrograph of Avian
influenza A H5N1 viruses (seen in gold) grown in MDCK cells (seen in green).
Credit: Cynthia Goldsmith/CDC
Yet despite the fact that the H5N1 avian influenza
has killed 60 percent of the 650 humans known to be infected since it was
identified in Hong Kong 17 years ago, the "bird flu" virus has yet to evolve a
means of spreading easily among people.
Now Dutch researchers have found that the virus
needs only five favorable gene mutations to become transmissible through
coughing or sneezing, like regular flu viruses.
World health officials have long feared that the
H5N1 virus will someday evolve a knack for airborne transmission, setting off a
devastating pandemic. While the new study suggests the mutations needed are
relatively few, it remains unclear whether they're likely to happen outside the
"This certainly does not mean that H5N1 is now more
likely to cause a pandemic," said Ron Fouchier, a virologist at Erasmus
University Medical Center in Rotterdam, Netherlands, and co-author of the study
published Thursday in the journal Cell. "But it does mean that we should not
exclude the possibility that it might happen."
As with many other influenza studies, the scientists
used ferrets as the stand-in for humans, because their immune system responds
similarly to the disease.
Prior research had established that H5N1 could
become contagious in ferrets if the virus was passed through a succession of
animals, essentially forcing the virus to evolve at an accelerated rate. In
those experiments, Fouchier and his colleagues found that the newly contagious
viruses had accumulated nine or more mutations.
In the new study, the authors set out to determine
the minimum number of mutations necessary for airborne infection.
To do this, the researchers took a strain of the
virus that had previously infected a human and altered its genes in the lab.
Then they sprayed the altered version of the virus into a ferret's nose and
placed the animal in a specially constructed cage with a second ferret who had
not been exposed to the virus.
The layout of the cages prevented direct contact
between the animals, but allowed them to share airflow. When the healthy ferret
developed flu symptoms - ruffled fur, loss of appetite and lack of energy -
researchers knew the virus had spread through the air.
By exposing ferrets and human tissue samples to a
variety of genetically altered viruses, study authors identified five key gene
Two of them improved the virus' ability to latch
onto cells in the animal's upper respiratory tract. Once there, it could enter
the cell, disgorge its genetic material and cause the cell to mass-produce
copies of the virus.
"Another mutation increases the stability of the
virus," Fouchier said. "The remaining mutations enable the virus to replicate
Virologists who were not involved in the study said
the findings were important, as they provided health authorities with a means of
discerning whether mutations observed in the wild are dangerous to people.
"This is important work," said Yoshihiro Kawaoka, a
virologist at the University of Wisconsin School of Veterinary Medicine. "This
could contribute to surveillance of
avian influenza viruses in nature."
Richard Webby, a virologist at St. Jude Children's
Research Hospital in Memphis, said that although the study provided a valuable
list of genetic traits to look for, the most important question for scientists
and health officials remained unanswered.
"The biggest unknown is whether the viruses are
likely to gain the critical mutations naturally," Webby said. "If they can
appear readily, then it is very worrisome. If not, then there's still a major
hurdle that these viruses have to get over to become human-transmissible."
Fouchier, Kawaoka and other researchers touched off
an international biosecurity furor in 2011 when they demonstrated that the H5N1
virus could be made transmissible among ferrets. As a result of the controversy,
the U.S. National Science Advisory Board for Biosecurity asked the virologists
to omit some details of their work before publishing it in the journals Science
and Nature. Scientists responded by imposing a temporary moratorium on their
Also, because of the Dutch government's concern that
virus could be weaponized, it successfully sued Fouchier and now requires
him to apply for and receive an "export permit" before publishing his studies.
Fouchier, who obtained such a permit for the Cell
study, said he did not expect it to ignite the same amount of controversy as his
"Certainly, there are still some people that would
prefer that this type of research be discontinued," Fouchier said. "We will
continue the debate with these people, but we have to realize that it is
impossible to reach a global consensus on everything - or anything."
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