Scientists have identified potential
biomarkers in nonhuman primates exposed to Ebola virus (EBOV) that
appeared up to four days before the onset of fever, according to
research published today in the journal Science Translational Medicine.
The work, a collaboration between the U.S. Army Medical Research
Institute of Infectious Diseases (USAMRIID) and Boston University (BU),
could pave the way for developing diagnostic tools to identify EBOV
infection in humans even before symptoms appear. Such tools would be
invaluable in limiting the spread of disease where there are cases of
known potential exposure to the virus, according to USAMRIID
investigator Sandra L. Bixler, Ph.D., the paper's co-first author.
Bixler said previously developed animal models of EBOV infection have
an acute disease course lasting only 7-10 days on average. This makes
therapeutic intervention challenging, since the timeframe for
administering treatment is very short. In addition, such models are
based on high viral doses and are uniformly lethal, which does not
reflect the variable and comparatively extended time to disease onset
seen in humans.
"Those models make sense for testing vaccines and therapeutics,"
Bixler commented. "But for human infection, they don't really match what
we see in the field -- especially given what we've learned from the
most recent Ebola virus disease outbreak in Western Africa."
So Bixler and USAMRIID colleague Arthur J. Goff, Ph.D., decided to
investigate alternative models that could still replicate human
infection while extending the disease course. Instead of challenging the
animals via injection, which is a standard laboratory model, they
tested the intranasal route -- which would be more likely to occur in a
natural outbreak where people may be exposed to infected bodily fluids.
The team designed a study using a lower dose of EBOV in 12 cynomolgus
macaques. The animals, exposed by intranasal infection and closely
monitored for signs of disease, fell into four categories. Three
succumbed to disease in the usual timeframe of 7-10 days following
infection; four had a delayed onset of 10-15 days; three were late-onset
(20-22 days); and two survived.
"We were then faced with the challenge of teasing apart any
differences between acute versus delayed disease onset, and survivors
versus non-survivors," said Louis A. Altamura, Ph.D., one of the
USAMRIID scientists who performed gene expression profiling to monitor
the host response via changes in RNA transcripts over time. Thanks to a
long-standing collaboration between USAMRIID and BU, investigators at
USAMRIID's Center for Genome Sciences, along with BU scientists John H.
Connor, Ph.D., and Emily Speranza, Ph.D., performed further genomic data
analysis and began to look for early markers of infection.
What they found -- in all the animals except the two survivors --
were interferon-stimulating genes that appear prior to infection with
Ebola virus. Importantly, the genes can be detected four days before the
onset of fever, which is one of the earliest clinical signs of EBOV
exposure. When Speranza compared the results to humans, using Ebola
patient blood samples from the most recent outbreak, she found the same
pattern.
"This demonstrates that lethal Ebola virus disease has a uniform and
predictable response to infection, regardless of the time to onset,"
commented Gustavo Palacios, Ph.D., who directs USAMRIID's Center for
Genome Sciences. "Furthermore, expression of a subset of genes could
predict disease development prior to other host-based indications of
infection, such as fever."
EBOV causes severe hemorrhagic fever in humans and nonhuman primates
with high mortality rates and continues to emerge in new geographic
locations, including Western Africa, the site of the largest recorded
outbreak to date. More than 28,000 confirmed, probable and suspected
cases have been reported in Guinea, Liberia and Sierra Leone, with more
than 11,000 reported deaths, according to the World Health Organization
(WHO). Today, WHO estimates that there are over 10,000 survivors of
Ebola virus disease.
Research on Ebola virus is conducted under Biosafety Level 4, or
maximum containment conditions, where investigators wear
positive-pressure "space suits" and breathe filtered air as they work.
USAMRIID is the only laboratory in the Department of Defense with
Biosafety Level 4 capability, and its research benefits both military
personnel and civilians.
Source of Research: US Army Medical Research Institute of Infectious Diseases
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