Network-driven analysis of human-Plasmodium falciparum interactome: processes for malaria drug discovery and extracting in silico targets

Abstract

Background: The emergence and spread of malaria drug resistance have resulted in the need to understand disease mechanisms and importantly identify essential targets and potential drug candidates. Malaria infection involves the complex interaction between the host and pathogen, thus, functional interactions between human and Plasmodium falciparum is essential to obtain a holistic view of the genetic architecture of malaria. Several functional interaction studies have extended the understanding of malaria disease and integrating such datasets would provide further insights towards understanding drug resistance and/or genetic resistance/susceptibility, disease pathogenesis, and drug discovery.

Methods: This study curated and analysed data including pathogen and host selective genes, host and pathogen protein sequence data, protein-protein interaction datasets, and drug data from literature and databases to perform human-host and P. falciparum network-based analysis. An integrative computational framework is presented that was developed and found to be reasonably accurate based on various evaluations, applications, and experimental evidence of outputs produced, from data-driven analysis.

Results: This approach revealed 8 hub protein targets essential for parasite and human host-directed malaria drug therapy. In a semantic similarity approach, 26 potential repurposable drugs involved in regulating host immune response to inflammatory-driven disorders and/or inhibiting residual malaria infection that can be appropriated for malaria treatment. Further analysis of host-pathogen network shortest paths enabled the prediction of immune-related biological processes and pathways subverted by P. falciparum to increase its within-host survival.

Conclusions: Host-pathogen network analysis reveals potential drug targets and biological processes and pathways subverted by P. falciparum to enhance its within malaria host survival. The results presented have implications for drug discovery and will inform experimental studies.

Keywords: Drug resistance; Gene ontology; Genomics; Malaria; Multi-omics; Protein–protein interaction.

Fig. 1

An overview of the approach implemented in this study

Fig. 2

A Assembled parasite network and B Functional interactions between C6KTD2 and C6KTB7 subnetwork within the parasite network. The nodes common to the subnetworks are coloured in yellow

Fig. 3

A Different distributions of disease similarity scores obtained in terms of frequencies (proportions) of disease matches vs similarity scores between disease-associated processes. The bigger rectangular bar indicates the threshold for the similarity between disease pairs of which the enriched similarity score (ESS) were used for further analysis. B Distributions of drug similarity scores obtained in terms of the relative frequency of drug matches against functional similarity scores between candidate gene and drug. The bigger rectangular bar indicates the threshold for the similarity between drug pairs of which the enriched similarity score (ESS) were used for further analysis

Fig. 4

A Functional interactions between C6KTD2 and C6KTB7 subnetwork in the unified host–pathogen functional network. The shared host proteins (yellow nodes) are involved in protein ubiquitination, positive regulation of cell apoptotic process, signal transduction, regulatory processes, and histone methylation. B Predicted shortest path network that could influence resistance and parasite adaptiveness between C6KTB7 (green node) and O00206 (bottom sky blue node) via co–targets (central sky blue nodes) in the host–pathogen network. C Predicted shortest path network that could influence resistance and parasite adaptiveness between C6KTD2 (green node) and O00206 (bottom sky blue node) via mediators (central sky blue nodes) in the host–pathogen network

Fig. 4

A Functional interactions between C6KTD2 and C6KTB7 subnetwork in the unified host–pathogen functional network. The shared host proteins (yellow nodes) are involved in protein ubiquitination, positive regulation of cell apoptotic process, signal transduction, regulatory processes, and histone methylation. B Predicted shortest path network that could influence resistance and parasite adaptiveness between C6KTB7 (green node) and O00206 (bottom sky blue node) via co–targets (central sky blue nodes) in the host–pathogen network. C Predicted shortest path network that could influence resistance and parasite adaptiveness between C6KTD2 (green node) and O00206 (bottom sky blue node) via mediators (central sky blue nodes) in the host–pathogen network