Scientists have identified a key molecule involved in the development of cerebral malaria, a deadly form of tropical disease. The study identifies a potential drug target and way forward toward alleviating this condition for which few targeted treatments are available.
In studies with mice, investigators discovered that the EphA2 protein is important for the onset of the leaky brain, a hallmark symptom of cerebral malaria.
The team also demonstrated that blocking EphA2 with different drugs prevented this dangerous symptom from occurring. According to the researchers, the findings indicate that a similar therapeutic strategy could potentially prevent the disease in humans.
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“The advance is really significant,” says Tracey Lamb, senior author of the study and associate professor in Pathology at the University of Utah Health.
“New targets to block a leaky brain in malaria are urgently needed to prevent mortality from cerebral malaria.”
The research, led by scientists at the University of Utah Health in collaboration with Centre Pasteur du Cameroun in Cameroon, is published in the journal PLOS Pathogens.
Cerebral malaria strikes more than 575,000 each year, disproportionately affecting young children in sub-Saharan Africa.
Researchers took note of EphA2 when they saw that the molecule became activated at the site of the blood-brain barrier just prior to its breakdown.
Further investigation showed that EphA2 disrupts the blood-brain barrier by loosening the tight junctions between cells, removing the glue that keeps these cells bound to each other.
With a key player identified, the scientists wondered whether blocking EphA2 would protect the blood-brain barrier during infection. Treating infected mice with two different agents showed this seems to be the case.
One agent was a repurposed cancer drug, Nilotinib, that inhibits several molecules including EphA2. The second was an engineered protein that specifically blocked molecules called ephrin ligands that will interact with EphA2 and prevent its activation.
“Usually children are not brought in to the clinic until they’re already experiencing symptoms of malaria,” says Thayer Darling, who carried out the research as a graduate student with Lamb.
“We’re hopeful that therapeutics that target EphA2 may be able to prevent cerebral malaria in children after the onset of those initial symptoms.”
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The work was primarily conducted in laboratory mice but additional results show clinical relevance. Blood from children with symptoms of cerebral malaria has elevated levels of an Ephrin protein that binds EphA2. Finding the marker in these children suggests the same pathway mediates the disease in both mice and humans.
“Understanding how infection with malaria parasites can lead to deleterious neurological conditions is key to discovering new therapeutic means to curb malaria-associated deaths globally,” says co-author Lawrence Ayong, Ph.D., a professor at Centre Pasteur du Cameroun.
“This research is very exciting and leads the way for future studies focused on modulating the activity of this protein in humans as a way to prevent malaria-associated deaths in children.”
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