Researchers have made a promising breakthrough in the fight against severe malaria, a disease primarily caused by the parasite Plasmodium falciparum. This parasite infects and alters red blood cells, making them adhere to the walls of tiny blood vessels in the brain. This phenomenon impairs blood flow, resulting in brain swelling and potentially life-threatening cerebral malaria.
The culprit behind these dangerous alterations lies within a family of approximately 60 virulent proteins known as PfEMP1, which appear on the surface of the infected red blood cells. Certain types of PfEMP1 proteins bind with a human protein called EPCR, located on the cells lining blood vessels, leading to damage and severe complications associated with malaria.
Growing older, African children slowly develop immunity, with teenagers and adults rarely experiencing lethal disease complications. It is believed that antibodies targeting PfEMP1 mediate this protective immunity. Despite the high variability of PfEMP1, which has long complicated attempts to target it via vaccines, an international team of researchers has made a groundbreaking discovery.
Advanced immunological screening methods, spearheaded by the University of Texas, enabled the team to identify two examples of human antibodies that effectively target various versions of the PfEMP1 protein. These antibodies zero in on a segment of the protein known as CIDRα1, which interacts with the EPCR receptor. Maria Bernabeu, co-senior author of the study and Group Leader at EMBL Barcelona, expressed initial skepticism but later excitement over these findings.
The challenge was testing whether these antibodies could block EPCR binding in living blood vessels, a task unsuitable for animal models due to species-specific differences in the parasite's proteins. To navigate this obstacle, researchers developed a unique laboratory method to grow a network of human blood vessels, allowing human blood infected with live parasites to pass through, effectively reconstructing the disease in vitro.
Using organ-on-a-chip technology, the team recreated 3D brain microvessels infected with malaria parasites. Upon introducing the two antibodies into this system, they observed a significant reduction in the infected cells' ability to adhere to the vessels, demonstrating potential to prevent the blockage leading to severe symptoms. Viola Introini, a Marie-Skłodowska Curie postdoctoral fellow at EMBL Barcelona and co-first author of the work, highlighted the striking visual evidence of successful inhibition.
Collaborative analysis with the University of Copenhagen and The Scripps Research Institute revealed that these antibodies thwart parasite binding through a similar mechanism, recognizing three highly conserved amino acids on CIDRα1. This suggests a common method of acquired immunity to severe malaria, offering new perspectives for creating a PfEMP1-based vaccine or other therapies targeting severe malaria.
"This study opens the door to targeting new ways of protecting people from severe malaria, like a vaccine or other treatments," stated Maria Bernabeu. She emphasized the importance of international and interdisciplinary collaboration in tackling complex diseases like malaria. The study exemplifies how tissue engineering and organ-on-a-chip technology permit comprehensive disease study and provide valuable platforms for vaccine candidate screening.
This research marks significant progress toward developing effective interventions against malaria, a disease that continues to pose major health challenges globally.
