A hidden chapter in the playbook

Malaria is a significant global health burden, with millions of people affected each year ¹. This challenge is compounded by parasite resistance to the current first-line antimalarial drug ^2,3 and the malaria vaccine’s low efficacy ⁴. In a bid to uncover new ways to combat this disease, efforts have been delving into the genetics of the deadly parasites that cause malaria. Our recent study has shed light on the role of PRMT5, an enzyme present in the most virulent malaria parasite Plasmodium falciparum. PRMT5 is one the members of the PRMT protein family that mediate post-translational modifications which regulate gene expression in various organisms.

A collaborative team effort and the resourceful Genomics Program Core facility at the University of South Florida embarked on this exploratory journey and executed this study. The study was entirely lab-based and it occasionally involved cultivating copious amounts of malaria parasites within the confined walls of tissue flasks. These clever little creatures can even be cultured for multiple generations by using human red blood cells as the hosts. Malaria parasites are the ultimate squatters. They are obligate intracellular parasites that have become the true connoisseurs of host accommodation. When it comes to houseguests, these parasites sure know how to overstay their welcome.    

We meticulously explored the inner workings of this enzyme to understand its functions on the parasite's biology. By employing a range of sophisticated techniques, including genetic disruption, transcriptome analysis, interactome assays, and global chromatin profiling, we delved deep into the functions of PfPRMT5. The results revealed both familiar and unexpected roles of this enzyme in the parasite’s survival and interactions with the host.

The functions of PfPRMT5

We have traced PfPRMT5’s multifaceted functions in the malaria parasite's intricate machinery. By disrupting PfPRMT5 we comprehensively assign its critical roles highlighted below;

1. A conserved role in RNA Splicing:

One of the key findings is the conserved role of PfPRMT5 in RNA splicing, a fundamental process in gene expression. While this process is not entirely new in studies on PRMTs, understanding its mediators and significance within the malaria parasite sheds new light on the intricate mechanisms underlying the parasite’s survival. RNA splicing plays a vital role in gene expression and host interaction processes, making PfPRMT5 an intriguing target for exploration. Similar to its counterparts in model organisms, PfPRMT5 influences the way genetic information is processed and handed down in P. falciparum, highlighting the shared importance of this mechanism across different species.

2. A unique role in host cell invasion:

Perhaps the most captivating finding in our study was the parasite-unique role of PfPRMT5 in regulating the invasion process. When malaria parasites invade and hijack host red blood cells to propagate, this stage is called the asexual stage in the parasite’s development. It is cyclic, very destructive and it is the stage that is clinically relevant in disease manifestation. The invasion of host red blood cells is a complex process, and PfPRMT5 emerges as another puppeteer in this enigmatic dance. Once settled inside the host cell, we revealed that the parasite’s enzyme interacts with key transcription factors and modulates the structure of the parasite's DNA thus impacting the expression of invasion-related genes as the parasite matures and prepares to invade new red blood cells. Disrupting PfPRMT5 compromises the parasite's ability to invade cells effectively. By unraveling the mysteries of PfPRMT5's involvement in invasion, we are edging closer to identifying potential vulnerabilities that could be exploited to develop novel antimalarial strategies.

3. The PfPRMT5-histone axis:

Histones, the proteins that package DNA within cells act as crucial regulators of gene activity, and PRMT5 adds specific marks to these proteins affecting their function. We investigated how PfPRMT5 interacts with parasite histones. Our biochemical assays and chromatin profiling experiments revealed that PfPRMT5 influences specific chemical modifications on histones both in vitro and in vivo, which in turn, impact gene expression. Intriguingly, when PfPRMT5 is disrupted, there is a reduction in a specific active mark known as H3R2me2s, which is associated with gene activation. This finding shows that PfPRMT5 plays a significant role in controlling gene expression, influencing the malaria parasite's ability to adapt and survive within its host.

4. The PfPRMT5's network

PfPRMT5 does not work in isolation but forms intricate connections with other molecules, influencing diverse aspects of the malaria parasite's biology. We dissected the interactome which indicated that PfPRMT5-associated proteins are involved in multiple cellular pathways. These interactions involve critical processes such as RNA splicing, transcription, DNA replication, and translation. 

In the fight against malaria, every new revelation brings us closer to the enemy line. The discoveries surrounding PfPRMT5 and unraveling its functions in RNA splicing, invasion regulation, and its intricate network of interactions enhance our understanding of the malaria parasite's biology providing crucial knowledge for prioritization of PfPRMT5 as a druggable target.

read about this story in detail here: https://www.nature.com/articles/s42003-023-05038-z

References

1. World malaria report 2022. (2022).
2. Ashley, E. A. et al. Spread of Artemisinin Resistance in Plasmodium falciparum Malaria . N. Engl. J. Med. 371, 411–423 (2014).
3. Dhorda, M., Amaratunga, C. & Dondorp, A. M. Artemisinin and multidrug-resistant Plasmodium falciparum - a threat for malaria control and elimination. Curr. Opin. Infect. Dis. 34, 432–439 (2021).
4. World Health Organization. Full Evidence Report on the RTS,S/AS01 Malaria Vaccine. SAGE Yellow B. Oct. 2021 1–90 (2021).