A blood-brain barrier spheroid is projected. The red blood cells are from P. falciparum. Malaria has threatened mankind for thousands of years.
220 million clinical cases and 400,000 deaths occurred in the previous year, with the majority of cases occurring in the WHO African Region, according to the latest WHO World Malaria Report published in November 2020. While researchers are working to provide therapies and develop vaccines to help treat this rampant disease, understanding the underlying mechanisms that cause disease severity is important. Malaria is caused by a single-celled parasites called Plasmodium, which can cause different forms of the disease.
Malaria can cause severe cases if it leads to infections in the body's major organs and if it is caused by the agent of Malaria tropica. Asexual reproduction is possible via the invasion of red blood cells by female Anopheles mosquitoes. The majority of disease symptoms occur when this is triggered.
Cerebral Malaria is caused by red blood cells obstructing blood circulation within brain blood vessels. The swelling and inflammation in the brain can have serious consequences for the patient. It is important to understand the origin and development of cerebral malaria to save lives.
A team of international researchers led by Professors Anja Jensen and Yvonne Adams from the University of Copenhagen set out to do this. The study was published in the Journal of Experimental Medicine. The red blood cells are taken up by the endothelial cells in the bloodâbrain barrier, which protects the brain against invasion.
There were red blood cells that were carrying parasites. Red blood cells are the primary source of oxygen for the body. Old red blood cells are removed from blood circulation after 120 days, an important task carried out by the spleen, which not only ensures a proper oxygen supply but also aids in mitigates infections, as the cells will be eliminated before the disease can ramp up.
This process is detrimental to malaria parasites and they need to circumvent it at all costs to survive. The parasites allow the presentation of their own virulence factors on the surface of the red blood cells that they had caused. The action trick the body and its army of immune cells, saving the cells from being removed from the blood by the spleen.
One of the parasites, the P. falciparum erythrocytes, is capable of producing not just one version of it, but different versions that form what biologists call a "protein family" Every member of the family is a part of the malaria parasites' genome, but only one version of the family is visible on the surface of the red blood cells. Individual parasites are able to switch the PfEMP1 version they present on the surface of the red blood cell in order to avoid detection by the immune system, making it even more interesting. The parasites can continue with red blood cell infections.
In addition to helping the red blood cells avoid elimination, the PfEMP1 proteins allow them to bind to different types ofreceptors found on the endothelial cells of different organs, such as the brain. The binding to the cells is determined by the version on the red blood cell surface. The red blood cell was taken up by an endothelial cell.
In 2015, they spotted P. falciparum in red blood cells within human brain endothelial cells, which is a rather unexpected observation because Malaria parasites have been shown to only affect red blood cells and hepatocytes. The novel observation was supported by pathologists who had seen it before. Jensen and Adams theorize that the malaria parasites might be triggering the ability of the endothelial cells to remove damaged red blood cells and clear blood clot from the body by using members of the PfEMP1 protein family.
The red blood cells that presented a particular version of PfEMP1 could bind the ICAM-1 and EPCR on the surface of the endothelial cells. The cerebral malaria episodes were connected to this event. The team used a spheroid model to study the phenomenon at the bloodâbrain barrier.
Cells that grow in the laboratory form a single layer. The advantage of the spheroid model is that it allows cells to grow into a 3D cluster, which is an elegant way to mimic the bloodâbrain barrier outside of the human body. The spheroid model gave a possible explanation for the route to brain infections.
It was shown that the red blood cells that have parasites on their surface are taken up and put down by the endothelial cells. The doorway to the brain may be opened even further when the endothelial cells swell. The authors don't know if this can be linked to the swelling of the brain in patients with severe malaria.
Jensen and Adams want to look closer at the interaction between red blood cells and endothelial cells in order to gain more detailed understanding of cerebral malaria in order to provide a platform for the development of better therapies and vaccines. Understanding how the malaria uses its own versatile toolbox of proteins to facilitate its absorption by cells and gain access to the brain is an important first step in that direction. In the Journal of Experimental Medicine, Yvonne Adams, et al., describe how the erythrocytes of the plasmodium falciparum strain cause cell swelling and disrupt the bloodâbrain barrier in cerebral malaria.
There is a DOI: 10.1084/jem.