Malaria’s Remodeling Job Protects against Immunological Scrutiny

While much of the world has rightfully focused its immediate attention on the coronavirus pandemic that has impacted much of the planet, one of the oldest leading causes of death annually still lurks in the shadows…quite literally. Malaria, which causes an inordinate amount of mortality and morbidity each year, is spread between humans by the world’s deadliest animal—the mosquito—and has been estimated to have wiped out half of all human existence since the Stone Age. Having a greater understanding of the molecular cell biology for this parasitic disease is the key to unlocking new therapeutics to treat and ultimately stop its spread.

Researchers have known for decades that the most severe form of human malaria, caused by the species Plasmodium falciparum, does extensive modifications of erythrocytes upon invasion. Typically, the parasites use an array of proteins trafficked to the erythrocyte cell surface to make the cell “sticky” and able to cling to peripheral endothelial tissue, avoiding the host immune system. When these modified sticky cells aggregate in the cerebral endothelium (cerebral malaria) or placental tissue, they can often cause fatal blood clots. Now, a team of investigators at the Francis Crick Institute has published new findings that identify how the parasite controls the red blood cell modification process.

“This malaria parasite species is able to use a number of different variants of the same protein to make red blood cells sticky,” explained co-lead study investigator Heledd Davies, PhD, a postdoc in the Signaling in Apicomplexan Parasites Laboratory at the Crick. “So, if the body develops antibodies that stop one variant working, the parasite can simply switch to another one, leading to a constant arms race.”

Davies continued that “a potentially more effective route for therapies could be to target the mechanism malaria uses to transport the proteins to the cell’s surface, as blocking it would reduce symptoms and allow the body to clear the parasites.”

Findings from this new study were published recently in Nature Microbiology  through an article entitled “An exported kinase family mediates species-specific erythrocyte remodeling and virulence in human malaria.” In the study, the authors identified proteins, so-called kinases, which are involved in getting the sticky proteins to the cell surface. Kinases are enzymes that can turn many other proteins on or off, and often regulate essential processes in cells.

“[Parasite] virulence is closely linked to the increase in rigidity of infected erythrocytes and their adhesion to endothelial receptors, obstructing blood flow to vital organs,” the authors wrote. “Unlike other human-infecting Plasmodium species, P. falciparum exports a family of 18 FIKK serine/threonine kinases into the host cell, suggesting that phosphorylation may modulate erythrocyte modifications.”

“These kinases are not released by other strains of malaria that infect humans, so we predicted that they are some of the factors that make this species deadlier,” Noted Hugo Belda, co-lead author and PhD student in the Signaling in Apicomplexan Parasites Laboratory at the Crick.

The study authors went on to describe their work, stating that “we reveal substantial species-specific phosphorylation of erythrocyte proteins by P. falciparum but not by Plasmodium knowlesi, which does not export FIKK kinases. By conditionally deleting all FIKK kinases combined with large-scale quantitative phosphoproteomics, we identified unique phosphorylation fingerprints for each kinase, including phosphosites on parasite virulence factors and host erythrocyte proteins. Despite their non-overlapping target sites, network analysis revealed that some FIKKs may act in the same pathways. Only the deletion of the non-exported kinase FIKK8 resulted in reduced parasite growth, suggesting the exported FIKKs may instead support functions important for survival in the host.”

The research team was encouraged by their findings and are looking forward to continuing their work with the hope of finding a potentially viable therapeutic target.

“In our research, we tested what happened when we removed different protein kinases from the parasite, while it is living in human blood,” concluded senior study investigator Moritz Treeck, PhD group leader in the Signaling in Apicomplexan Parasites Laboratory at the Crick. “One protein played an important role in controlling cell stickiness, while others may be required for yet unknown aspects of the parasite’s biology. This is very exciting and will help to better understand the disease mechanism.”