Abstract
BackgroundThe 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.MethodsThis 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.ResultsThis 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.ConclusionsHost–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.
Highlights
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
With a defined similarity score threshold of 0.31099875 (Fig. 3B) based on similarity in terms of processes the drugs are involved in, the results revealed 26 potential repurposable drugs (Additional file 9: Table S6).The repurposable drugs categorized as known anti-malarial, monoclonal antibodies, immunomodulators, herbs, natural products, Janus kinase inhibitors, and thrombolytic agents act as either antagonist, agonists, inhibitors, or precursors targeting genes over-represented in immune response and cytokine-mediated signalling processes
Aminake et al [68] explored the role of the proteasome of P. falciparum for malaria drug research and revealed C6KTB7 as a component of the ubiquitin– proteasome which could serve as a promising multi-stage target, a supporting results presented by Chung et al [70]
Summary
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. ACT was adopted in Africa after the decline in efficacy of previous widely used anti-malarial drugs, including chloroquine and sulfadoxine-pyrimethamine (SP) [2] This was to ensure that, each component of the combinatorial drug acts through different mechanisms within the parasite, aiming to significantly reduce the likelihood of the emergence of multi-drug resistant parasites. Another study conducted in Northern Uganda has reported independent emergence and local spread of artemisinin-resistant parasite driven by mutations in the A675V or C469Y allele in the kelch gene [8]. These pieces of evidence suggest that artemisinin resistance has emerged independently in Eastern Africa
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