Discovery of how parasite sticks to blood vessels could lead to new means to combat malaria.
Malaria parasites grow in red blood cells and stick to the endothelial lining of blood vessels through a large family of parasite proteins called PfEMP1. This way, the parasite avoids being carried with the blood to the spleen, where it would otherwise be destroyed. One of the most aggressive forms of malaria parasite binds in brain blood vessels, causing a disease called cerebral malaria.
In 2012, three groups of researchers, including the teams at the University of Copenhagen and Seattle Biomedical Research Institute, showed that a specific type of PfEMP1 protein was responsible for cerebral binding and other severe forms of malaria infection. However, until now, the receptor to which it binds remained unknown, and the next big question was to determine which receptors the infected red blood cells were binding to.
“The first big challenge was to generate a full-length PfEMP1 protein in the laboratory,” says Assistant Professor Louise Turner at the University of Copenhagen. “Next, we utilized a new technology developed by Retrogenix LTD in the United Kingdom to examine which of over 2,500 human proteins this PfEMP1 protein could bind to.” Of the 2,500 proteins screened, a receptor called endothelial protein C (EPCR) was the single solid hit.
“A lot of work then went into confirm this binding in the lab and not least to show that parasites from non-immune children with severe malaria symptoms in Tanzania often bound EPCR,” she continues.
“It was a true eureka moment,” says Assistant Professor Thomas Lavstsen. “Under normal conditions, ECPR plays a crucial role in regulating blood clotting, inflammation, cell death and the permeability of blood vessels. The discovery that parasites bind and interfere with this receptor´s normal function may help us explain why severe symptoms of malaria develop."
Severe malaria symptoms such as cerebral malaria often result in minor blood clots in the brain. One of our body´s responses to malaria infection is to produce inflammatory cytokines, but too much inflammation is dangerous, describes Professor Joseph Smith, from the Seattle Biomedical Research Institute.
“ECPR and a factor in the blood called protein C act as a ‘brake’ on blood coagulation and endothelial cell inflammation and also enhance the viability and integrity of blood vessels, but when the malaria parasites use PfEMP1 to bind EPCR, they may interfere with the normal function of EPCR, and thus the binding can be the catalyst for the violent reaction,” he explains.
“Now that we know the pair of proteins involved, we can begin zooming further in to reveal the molecular details of how malaria parasites grab onto the sides of blood vessels. We want to know exactly which bits of the parasite protein are needed to bind to the receptor in the blood vessel wall. Then, we can aim to design vaccines or drugs to prevent this binding.”
Via
Dr. Stefan Gruenwald,
W H Unsell