Decrypting the complexity of the human malaria parasite biology through systems biology approaches

Abstract

The human malaria parasite, Plasmodium falciparum, is a unicellular protozoan responsible for over half a million deaths annually. With a complex life cycle alternating between human and invertebrate hosts, this apicomplexan is notoriously adept at evading host immune responses and developing resistance to all clinically administered treatments. Advances in omics-based technologies, increased sensitivity of sequencing platforms and enhanced CRISPR based gene editing tools, have given researchers access to more in-depth and untapped information about this enigmatic micro-organism, a feat thought to be infeasible in the past decade. Here we discuss some of the most important scientific achievements made over the past few years with a focus on novel technologies and platforms that set the stage for subsequent discoveries. We also describe some of the systems-based methods applied to uncover gaps of knowledge left through single-omics applications with the hope that we will soon be able to overcome the spread of this life-threatening disease.

Keywords: Multiomic analysis; Omics; Plasmodium; malaria; systems biology.

FIGURE 1

Plasmodium Life Cycle. Illustration depicting Plasmodium parasite life cycle alternating from an invertebrate Anopheles (Left) host to a mammalian human host (Right).

FIGURE 2

Schematic representation of hierarchical chromatin organization along with the technologies applied for their characterization. The hierarchical chromatin landscape can be broken down to three major compartments. (A) Hi-C provide 3D spatial architectural landscapes of chromosomes within the cell. These chromatin architectural analyses uncover important chromosomal territories, topologically associating domain (TAD) and chromatin contacts required for gene regulation. (B) Chromosomal landscape is divided into territories of heterochromatin and euchromatin. The chromatin is regulated by histone modifying enzymes to open (euchromatin) or close (heterochromatin) chromatin boundaries. Tools such as ChIP-sequencing, MNase, FAIRE-seq, DNase-seq, ATAC-seq serve as important means to uncover important PTMS and gene regulators. (C) DNA sequencing platforms provide high-throughput WGS capable of identifying genomic variations such as SNPs and CNVs. Over the past decade these sequencing have evolved drastically in the depth of sequencing capabilities.

FIGURE 3

Schematic illustration of major tools and technologies used to characterize a cell’s transcriptome. Gene expression is a major factor of cell development, regulation, and response to stimuli. Thus, adaptations in tools and technologies have provided new opportunities to study a cell transcriptome at all stages pre and post transcriptional levels. Unique tools have now allowed for the capture of actively transcribing genes by targeting RNA-ribosome interactions. Other platforms seek to decipher RNA-protein interactions. RNA sequencing platforms have also shown great improvement overtime.

FIGURE 4

Systems-Wide Approach to Determine the Cell’s Functional Organization. Genomics, Transcriptomics, Proteomics, and Metabolomics based techniques are applied towards precision medicine against malaria. These multi-omics-based approaches are used to understand the intrinsic characteristics of the human host and Plasmodium involved in clinical malaria as well as the complex host-parasite interactions that occur. Complex mathematical models provide opportunities for precision based computational inferences to better uncover new potential drug targets. Ultimately, the integration of various layers of regulatory and structural and computational level analysis will help in developing precision medicine against malaria.