Researchers based at the National Institute of Immunology (NII), New Delhi, and Yenepoya University, Mangalore, have uncovered the crucial role of Protein kinase 2 (PfPK2) in malarial parasite development and invasion of host red blood cells, offering insights for potential therapeutic strategies. Depleting PfPK2 resulted in reduced invasion of host erythrocytes by the parasite and impaired its maturation in the host maturation, highlighting it as a promising target for new malaria drugs.
Understanding how malarial parasites affect our body is crucial for developing medical therapies. This battle between malarial parasites and the human body involves various signals and signalling molecules. One such signalling molecule, Protein kinase 2 (PfPK2), has gained a spotlight for being an indispensable enzyme in malarial parasite development and invasion of host red blood cells (RBCs) to establish infection. Researchers based at the National Institute of Immunology (NII), New Delhi, and Yenepoya University, Mangalore, recently published novel findings as the outcome of collaborative efforts.
Malaria remains one of the most life-threatening diseases with global tally of cases reaching approximately 247 million. Malarial infection begins with the bite of an infected Anopheles mosquito, which injects the plasmodium species in the form of sporozoites directly into the bloodstream. These sporozoites travel to and reside in the liver, multiplying asexually for seven to ten days without causing visible symptoms in the patient.
From the liver, the sporozoites transform and emerge as merozoites, eventually entering the bloodstream and infecting RBCs. Inside the RBCs, also known as erythrocytes, the merozoites replicate their genome and undergo several asynchronous asexual divisions, forming more merozoites. Rupture of the RBCs release the merozoites, leading to the invasion of other RBCs.
During this process, several signalling pathways are involved, including receptor-ligand binding interactions that facilitate the invasion process. Protein kinases, enzymes that phosphorylate proteins, are one of the many different protein families that play an essential role in these signalling pathways. Pushkar Sharma, NII, New Delhi, and the lead scientist of this study, said,
The previous studies suggested that PfPK2 might be indispensable for parasite survival. But its precise function remained unknown until elucidated in the present study.
Sharma further said, “Signalling pathways regulate most cellular processes in almost all organisms. As they still remain poorly defined in the human malaria parasite Plasmodium falciparum, a detailed understanding of these pathways will shed light on novel mechanisms involved in the parasite’s development. It will also pave the way for innovative therapeutic strategies”. The authors have used a conditional knockout strategy aka gene switch off and proteomics to elucidate the function of PfPK2.
Puran Singh Sijwali, Centre for Molecular & Cellular Biology, Hyderabad, who was not part of the study, said, “PfPK2, being a crucial enzyme with a key role in invading host cells, represents a promising target for developing new malaria drugs.” He proposed, “Researchers could explore this enzyme to search through inhibitor libraries targeting kinases. This may help identify potential lead inhibitors, which can then be optimised to develop potent drug-like compounds”.
The researchers have found that depleting PfPK2 resulted in a notable decrease in the ability of the parasite to invade host red blood cells (or erythrocytes). Further investigation, demonstrated that PfPK2 regulates formation of tight-junctions, which act like a bridge between the invading merozoite and the host erythrocyte.
Sharma added, “In collaboration with Keshava Prasad, Yenepoya University, Mangalore, we conducted comparative phosphoproteomics studies to identify PfPK2 substrates in the parasite.” The researchers noted a significant drop in the levels of cGMP, which may be via its ability to regulate guanylyl cyclase (GCa), a key enzyme for forming cGMP in the parasite, when PfPK2 was reduced. Their study also showed that the calcium release, crucial for host cell invasion, was also affected. Sijwali said,
Even today, our understanding of the basic biological processes of the malaria parasite is largely assumptive or based on the knowledge of similar processes in model organisms. So, research to better understand the basic biology of malaria parasite is necessary to identify targets of vaccine and drug development.
In the future, the research team is actively investigating the phospho-signalling networks involved in parasite division as they continue to unravel to unravel second messenger signalling pathways in parasite biology.