An image of the H1N1 influenza virus taken in the CDC Influenza Laboratory. Credit: Centers for Disease Control
In the fall of 1917, a new strain of
influenza swirled around the globe. At first, it resembled a typical flu
epidemic: Most deaths occurred among the elderly, while younger people
recovered quickly. However, in the summer of 1918, a deadlier version of the
same virus began spreading, with disastrous consequence. In total, the pandemic
killed at least 50 million people.
That two-wave pattern is typical of
pandemic flu viruses, which is why many scientists worry that the 2009 H1N1 flu
virus might evolve into a deadlier form.
H1N1, first reported in March 2009 in Mexico,
contains a mix of human, swine, and avian flu genes, which prompted fears that
it could prove deadlier than typical seasonal flu viruses. However, the death
toll was much lower than initially feared, in large part because the virus
turned out to be relatively inefficient at spreading from person to person.
In a new study from MIT, researchers
have identified a single mutation in the H1N1 genetic makeup that would allow
it to be much more easily transmitted between people. The finding, reported in Public Library of Science (PLoS) One,
should give the World Health Organization (WHO), which tracks influenza
evolution, something to watch out for, says Ram Sasisekharan, senior author of
“There is a constant need to monitor the
evolution of these viruses,” says Sasisekharan, the Edward Hood Taplin
Professor and director of the Harvard-MIT Division of Health Sciences and
Technology. Some new H1N1 strains have already emerged, and the key question,
Sasisekharan adds, is whether those strains will have greater ability to infect
WHO labs around the world are collecting
samples of human and avian flu strains, whose DNA is sequenced and analyzed for
potential mutations. However, it’s difficult, with current technology, to
predict how a particular DNA sequence change will alter the structure of
influenza proteins, including hemagglutinin (HA), which binds to receptors
displayed by cells in the human respiratory tract. Now that this specific HA
mutation has been identified as a potentially dangerous one, the WHO should be
able to immediately flag any viruses with that mutation, if they appear.
Identifying this mutation is an
important step because it is usually difficult to identify which of the many
possible mutations of the HA protein will have any impact on human health, says
Qinghua Wang, assistant professor of biochemistry at Baylor College of
Medicine. “These are exactly the types of mutations that we need to watch out
for in order to safeguard humans from future disastrous flu pandemics,” he
On June 11, 2009, about three months after the H1N1 virus first appeared, WHO
declared a level 6 pandemic alert. Nearly 5,000 H1N1 deaths were reported to
the WHO, and more than 400,000 cases were confirmed.
In July 2009, a team of researchers from
MIT, led by Sasisekharan, and the Centers for Disease Control and Prevention reported
in Science that the H1N1 virus was
much less easily passed from person to person than seasonal flu viruses and
earlier pandemic flu viruses such as the second wave of the 1918 strain.
Sasisekharan and CDC senior
microbiologist Terrence Tumpey had previously shown that a major factor in
flu-virus transmissibility is the structure of the HA protein, which is found
on the viral surface. The tightness of fit between HA and the respiratory cell
receptor determines how effectively the virus infects a host.
The 2009 H1N1 strain, like the first
wave of 1918 (known as the NY18 strain), does not bind efficiently. However, it
took only one mutation of the NY18 virus’ HA protein to become the much more
virulent SC18 strain, which caused the second wave.
In the new PLoS study, the MIT
researchers focused on a segment of the HA protein that they have shown affects
its ability to bind to respiratory cells. They created a virus with a single
mutation in that region, which replaced the amino acid isoleucine with another
amino acid, lysine. That switch increased the HA protein’s binding strength.
They also found that the new virus spread more rapidly in ferrets, which are
commonly used to model human influenza infection.
If such a mutant virus evolved, it could
generate a “second wave” like the ones seen in 1918 and in 1957 (known as the
“Asian flu”). “If you look at the history, it takes a very small change to
these viruses to have a dramatic effect,” Sasisekharan says.
The amino acid in question is located in
a part of the viral genome prone to mutate frequently, because it is near the
so-called antigenic site. Antigenic sites tend to evolve rapidly to escape such
antibodies, which is why flu vaccine makers have to use new formulas every
year. This year’s vaccine included a strain of H1N1, which is still circulating
around the world.
Filed Under: Drug Discovery