Boosting angiopoietin-1 (Ang-1) - a protective protein to stabilize blood vessels weakened by
malaria showed improved survival, revealed pre-clinical research.
Toronto General Research Institute
(TGRI) and the Sandra Rotman Centre for Global Health, University of
Toronto and University Health Network researchers describe in Science Translational Medicine
, 28 September 2016
how their approach bolsters the body's own capabilities to protect
itself against cerebral malaria, rather than solely targeting the
malaria parasites in the blood.
‘Bolstering angiopoietin-1 (Ang-1) - a protective protein in blood vessels helps the body protect itself against cerebral malaria.
Over 400,000 lives are lost each
year to severe and cerebral malaria, mainly among children in
sub-Saharan Africa. For children surviving cerebral malaria, up to
one-third may develop long-term neurological injury including epilepsy,
behavioural disorders and/or motor, sensory or language deficits.
by Dr. Sarah Higgins, now a Research Fellow at Harvard Medical School
and Beth Israel Deaconess Medical Center, and Dr. Kevin Kain, Science
Director, Tropical Disease Unit, Toronto General Hospital, University
Health Network, the researchers demonstrate how giving mice
angiopoietin-1 (Ang-1), a key protein which protects the lining in blood
vessels in humans and mice, when combined with the best antimalarial
drug artesunate, results in 100 per cent of mice surviving severe
malaria, compared to about 60% of the mice infected with malaria who
received artesunate alone.
Equally important, the research
also showed that Ang-1 preserves the blood-brain barrier, a critical
network of blood vessels that allows nutrients to cross over into the
brain, while keeping out foreign substances that may harm it. An
infection such as severe malaria causes changes in blood vessels,
resulting in a breakdown of the blood-brain barrier and brain injury.
protect against this injury, we recreated what the body produces,"
explains Dr. Higgins, "Ang-1 enables blood vessels to maintain normal
function and serves as a protective barrier for the brain." Dr. Higgins,
who did the research while a graduate student in the lab of Dr. Kevin
Kain, is the first author in the research paper entitled, "Dysregulation
of angiopoietin-1 plays a critical mechanistic role in the pathogenesis
of cerebral malaria."
In a series of elegantly designed
experiments, the team first tested 180 children aged one to 10 years
old, with severe cerebral malaria in Uganda, along with children who had
no or mild malaria. They found that those with severe and cerebral
malaria had significantly lower amounts of Ang-1.
The team then
went on to test mice with malaria and found that, similar to humans,
Ang-1 drops significantly in these mice. They also "knocked out" the
gene for Ang-1 in mice, and found that its protective effects
disappeared. In the final experiment, when the ill mice were injected
with Ang-1, in addition to the antimalarial medication, they survived
and had no brain injury.
The development of cerebral malaria is
not well understood, but research has shown that how an individual
responds to the illness is important in determining its severity and
outcome. Strategies which target only the parasite are not enough to
prevent complications and deaths in individuals with severe infection."Patients
often die from their response to the infection, rather than directly
from their infections," points out Dr. Kain, who is also the Director,
SA Rotman Laboratories at the Sandra Rotman Centre for Global Health and
Senior Scientist at TGRI.
"Our approach is about modifying 'us'
rather than solely focusing on drugs to kill microbes, and for
life-threatening infections like cerebral malaria, this strategy may
improve outcome while decreasing drug resistance," he says.
want to change the paradigm. Our primary goal should be about improving
survival and preventing brain injury, rather than a strict preoccupation
with antimicrobial drugs to kill bugs. Our findings have broad
implications for other life-threatening infections such as sepsis, toxic
shock, for which we currently have no specific treatments."
research was funded by the Canadian Institutes of Health Research,
Canada Research Chair (to Dr. Kevin Kain), and donations from Kim
Kertland and the Tesari Foundation.