Research
Our lab focuses on epigenetic and transcriptional regulation as potential avenues to disrupt the progression of this deadly parasite. To accomplish this, our research combines tools from functional genomics, molecular biology, biochemistry and computational biology to understand the fundamental molecular mechanisms underlying the development of this parasite.
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1. Epigenetics and Transcriptional Regulation
Role of epigenetic mechanisms towards regulation of the complex life cycle/pathogenesis of Plasmodium falciparum, the causative agent of malaria, has been poorly understood. To elucidate stage-specific epigenetic regulation, we performed genome-wide mapping of multiple histone modifications of P. falciparum. Our study reveals unique plasticity in the epigenetic regulation in P. falciparum which can influence parasite virulence and pathogenicity. The observed differences in the histone code and transcriptional regulation in P. falciparum and its host will open new avenues for epigenetic drug development against malaria parasite.
Model depicting differential occupancies of histone modifications and RNA polymerase II regulating transcription of housekeeping (top panel) and var (bottom panel) genes in P. falciparum
2. Mechanisms of Drug Resistance
Malaria parasites are constantly adapting to the drugs we used to eliminate them. Thus, when we use the drugs to kill parasites; with time, we select the parasites with the favourable genetic changes. Parasites develop various strategies to overcome exposure to the drugs by exhibiting the stress responses. The changes specific to the drug adapted parasites can be used to understand the mechanism of drug resistance generation.
Model showing the role and interplay of Kelch13, PI3K and PfGCN5 in artemisinin resistance generation.
3. Cellular Heterogeneity in unicellular parasite
The malaria parasite has a complex life cycle exhibiting phenotypic and morphogenic variations in two different hosts. Phenotypic cell-to-cell variability can be an important determinant of cellular adaptation, stress tolerance and immune evasion in the host. Our study suggests that the variability and versatility of the maintenance of cellular homeostasis should enable cells to survive under different stress conditions, and may act as an important stimulator of development of drug-resistance in Plasmodium falciparum.
Single-cell RNA sequencing (scRNA-Seq) identified a rare population (cluster 8) of cells which is emerged during temperature stress condition.
4. Genomic Epidemiology of P. falciparum
We intend to perform whole genome sequencing of the parasites strains collected from different regions across India. The epicentres of malaria in India are spaced out across vast distances which allow for speciation to yield changes in genomic organization. This gives rise to differential phenotypic profile of these parasites in terms of drug sensitivity, surface markers, etc. This shall enable understanding how the Indian strains have evolved in the global context and how they may respond to different drug regimes. Understanding the cohort specific differences in parasite strains may allow a better understanding of the differential dynamics of the resistance evolution trends.
Countries with indigenous cases in 2000 and their status by 2017 (Credit: WHO).