Researchers report that the discovery of a malaria protein that helps the parasite grow inside red blood cells and plays a key regulatory role in the parasite’s immune evasion tactics could pave the way for new vaccines or therapeutics to combat the deadly infection.

The protein, known as PfAP2-P, was previously identified in a King Abdullah University of Science and Technology (KAUST)-led study that explored malarial genes and proteins displaying rhythmic 24-hour expression patterns. This adaptation allows the parasite to synchronize its activities with those of the host during the human blood stage of its developmental cycle.

two scientists
The discovery of a recent malaria protein by Amit Kumar Subudhi, PhD, (left), and Arnab Pain, PhD, could lead to the development of vaccine-like immune triggers for warding off natural malaria infections in people. [KAUST; Anastasia Serin]

The team’s study “DNA-binding protein PfAP2-P regulates parasite pathogenesis during malaria parasite blood stages” appears in Nature Microbiology.

“Malaria-associated pathogenesis such as parasite invasion, egress, host cell remodelling and antigenic variation requires concerted action by many proteins, but the molecular regulation is poorly understood,” write the investigators.

“Here we have characterized an essential Plasmodium-specific Apicomplexan AP2 transcription factor in Plasmodium falciparum (PfAP2-P; pathogenesis) during the blood-stage development with two peaks of expression. An inducible knockout of gene function showed that PfAP2-P is essential for trophozoite development, and critical for var gene regulation, merozoite development and parasite egress.

“Chromatin immunoprecipitation sequencing data collected at timepoints matching the two peaks of pfap2-p expression demonstrate PfAP2-P binding to promoters of genes controlling trophozoite development, host cell remodelling, antigenic variation and pathogenicity. Single-cell RNA sequencing and fluorescence-activated cell sorting revealed de-repression of most var genes in Δpfap2-p parasites. Δpfap2-p parasites also overexpress early gametocyte marker genes, indicating a regulatory role in sexual stage conversion.

“We conclude that PfAP2-P is an essential upstream transcriptional regulator at two distinct stages of the intra-erythrocytic development cycle.”

The expression levels of PfAP2-P seem to peak first around 16 hours after the invasion of red blood cells and then again some 24 hours after that. These peaks coincide with the activation of genes linked to two crucial biological processes. The first is when malaria parasites coat the red cells they infect with various combinations of sticky proteins to elude immune recognition and the second when groups of young parasites prepare to exit one red blood cell and invade other uninfected red cells.

Molecular experiments

Amit Kumar Subudhi, PhD, a research scientist working with Arnab Pain, PhD, and his group, as well as with collaborators from various other KAUST labs, wanted to reveal PfAP2-P’s function.

Through a series of molecular experiments, they showed that PfAP2-P indeed serves as an essential regulator of multiple key biological processes of the parasites. The protein acts as both a repressor of genes involved in immune evasion and as a brake on genes associated with the parasite’s transition to its sexual stage of development.

The scientists also identified several novel proteins that are directly or indirectly regulated by PfAP2-P, a few of which could be targeted for future drug development. Moreover, they discovered that PfAP2-P acts as an activator of the proteins required for the parasite to exit infected red blood cells and invade new ones.

Perhaps the most promising discovery came from studies on mutant malaria parasites that lacked a working version of PfAP2-P. These parasites could not control the coordinated expression of highly variable sticky proteins at the surface of the red cells involved in skirting immune detection.

Red cells infected with these PfAP2-P–defective parasites expressed the full array of sticky surface proteins, rather than employing the usual tactic of “hide and seek” with the host immune recognition system. As a result, the PfAP2-P-defective parasites were readily recognized by malaria-destroying antibodies that, in principle, could help train the body to fend off naturally occurring malaria infections.

The KAUST researchers are currently exploring the potential of these mutant parasites as vaccine-like immune triggers for warding off natural malaria infections in people.

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