PfHDAC1 is a regulator of cell cycle in Plasmodium falciparum and drives the artemisinin resistance associated transcriptome

Abstract

Plasmodium falciparum is a deadly protozoan parasite and the causative agent of malaria which accounts for close to 200 million cases and 400,000 deaths every year (WHO World Malaria Report 2020). It has been identified to possess a tightly regulated gene expression profile which is integrally linked to its timely development during the intraerythrocytic stage. Epigenetic modifiers of the histone acetylation code have been identified as key regulators of the parasite’s transcriptome. In this study, we have characterised the solitary class I histone deacetylase, PfHDAC1 as an important regulator of numerous parasite genes/pathways implicated in antigenic variation/immune evasion, proteostasis and cell cycle regulation. Furthermore, inhibition of PfHDAC1 leads to a delayed progression through the intraerythrocytic development and even lower infection rates over the subsequent cycle. Conversely, overexpression of PfHDAC1 reversibly enhances the proliferation of the parasites. Interestingly, changes in cell cycle progression have been associated with resistance to artemisinin (ART) drug in P. falciparum. Population transcriptomics studies of artemisinin resistant parasites from the field have shown deregulation in the levels of PfHDAC1. We find that genetic manipulation as well as pharmacological targeting of PfHDAC1 abundance/activity resulted in enhanced survival of parasites under therapeutic ART dosage, essentially aiding drug resistance. To identify the transcriptional links between ART resistance and deregulation of PfHDAC1, we compared the transcriptional profile of ART resistant field isolates and parasites with deregulation of PfHDAC1. We identified a core set of biological pathways (upregulation of proteostasis, fatty acid biosynthesis, translation and downregulation of cell cycle, antigenic variation, host-pathogen interaction) matches with the transcriptome of PfHDAC1 deregulation. This in turn suggests that PfHDAC1 deregulation can account for the core conserved transcriptional changes that are the hallmark of ART resistance. In synopsis, PfHDAC1 is critically linked to governance of a host of important biological pathways in the parasite including cell cycle and its deregulation can facilitate rewiring of the parasite transcriptome in a way that allows drug resistance to emerge.