In a development that may add a piece of the puzzle
about why West Africa's Ebola outbreak was so much worse than
others involving the virus, researchers yesterday described
mutations that made it more capable of infecting
humans.
Adding weight to the findings, two different groups reported
similar discoveries involving the same mutation—A82V in the gene
that encodes the Ebola virus glycoprotein—in the same issue of the
journal Cell. One group was led by primarily by US researchers
based at the University of Massachusetts Medical School and
Harvard's Broad Institute, with the other a large international
team that includes scientists from the University of Nottingham and
the Pasteur Institute.
As the scope of the 2014-16 outbreak overwhelmed global health
systems, experts worried that each new infection was adding more
throws of the genetic dice, which could lead to changes enabling
the virus to spread more quickly. By the time the outbreak wound
down, more than 28,000 people were infected, including 11,000
people who died.
Jeremy Luban, MD, coauthor of the US-based study and professor
at the University of Massachusetts Medical School, said in a Cell
Press media release that Ebola is thought to circulate in an
unknown reservoir, with rare spillovers to people. "When the virus
does cross over, the effect has been devastating to those people
who are infected. Until recently, the human disease outbreaks have
been short lived, and the virus has had little opportunity to adapt
genetically to the human host."
First, the researchers examined publicly available Ebola genetic
sequences to look for mutations. They found that the A82V mutation
arose early in the outbreak, in early 2014 as the virus moved from
Guinea to Sierra Leone. They then used noninfectious virus material
containing the A82V mutation to see how it infected different
cells, the international-based group focusing in human and bat
cells, while the US investigators did their experiments on cells
from humans, non-human primates, and other mammal species.
Both teams found that the mutation enhanced the virus's ability
to infect cells only from humans and other primates, which they
said suggests that the increased infectivity they saw in human
cells could have helped fuel the spread of the virus.
Comparing the findings with how the outbreak unfolded, the US
team found that the A82V mutation was associated with a modest
increase in mortality.
Meanwhile, the international team looked for signs of adaptation
in Ebola's transition from bats, the presumed reservoir, to humans.
They found other mutations and changes linked to A82V, along with
hints that fruit bats, and not other species, are the likely Ebola
reservoir.
Jonathan Ball, PhD, coauthor of the international group's study
and professor of virology at the University of Nottingham, said in
the Cell Press release, "We found that as Ebola virus was spreading
from human to human, it apparently didn't have to worry about
maintaining its infectivity in bats."
In a commentary in the same issue of Cell, two experts wrote
that the studies provide the clearest example so far of Ebola's
functional adaptation to human hosts. The authors are Trevor
Bedford, PhD, and Harmit Malik, PhD, both with the Howard Hughes
Medical Institute at the Fred Hutchinson Cancer Research Center in
Seattle.
"It would appear that both studies have the 'smoking gun'
evidence to make the case for molecular adaptation in Ebola leading
to increased human virulence," they wrote, adding that "herculean
efforts" to sample and sequence the virus during the outbreak make
the new findings an example of "catching the virus in the act."
They point out, however, that it's difficult to connect a single
molecular change to the observed transmission patterns. Bedford and
Malik also said the results beg the question of why the new
mutation was more successful in its human host.
The researchers said they will continue their work to identify
how the mutations made Ebola more infectious for humans.
Luban said, "It's important to understand how these viruses
evolve during outbreaks. By doing so, we will be better prepared
should these viruses spill over to humans in the future."
In the study from Luban's group, the researchers said the
findings warrant follow-up with in vivo studies in high-containment
(biosafety level 4) labs and cell-culture studies to compare
different live Ebola variants.