Large–scale data–driven network analysis of human–plasmodium falciparum interactome: extracting essential targets and processes for malaria drug discovery

Plasmodium falciparum malaria is an infectious disease considered to have great impact on public health due to its associated high mortality rates especially in sub Saharan Africa. Falciparum drug resistant strains, notably, to chloroquine and sulfadoxine-pyrimethamine in Africa is traced mainly to Southeast Asia where artemisinin resistance rate is increasing. Although careful surveillance to monitor the emergence and spread of artemisinin-resistant parasite strains in Africa is on-going, research into new drugs, particularly, for African populations, is critical since there is no replaceable drug for artemisinin combination therapies (ACTs) yet.

About 600,000 significant SNPs (p-value< 0.05) from the summary statistics data were mapped to their associated genes, and 79 human-associated malaria genes were identified. The assembled parasite network comprised of 8 clusters containing 799 functional interactions between 155 reviewed proteins of which 5 clusters contained 43 key proteins (selective variants) and 2 clusters contained 2 candidate key proteins(key proteins characterized by high centrality measure), C6KTB7 and C6KTD2. The human network comprised of 32 clusters containing 4,133,136 interactions between 20,329 unique reviewed proteins of which 7 clusters contained 760 key proteins and 2 clusters contained 6 significant human malaria-associated candidate key proteins or genes P22301 (IL10), P05362 (ICAM1), P01375 (TNF), P30480 (HLA-B), P16284 (PECAM1), O00206 (TLR4). The generated host-pathogen network comprised of 31,512 functional interactions between 8,023 host and pathogen proteins. The study also explored the association of pfk13 gene within the host-pathogen and observed that pfk13 cluster with host kelch–like proteins and other regulatory genes but no direct association with our identified host candidate key malaria targets. Semantic similarity based approach was implemented complemented by Kappa and Jaccard statistical measure to identify 115 malaria–similar diseases and 26 potential repurposable drug hits that can be 3 appropriated experimentally for malaria treatment.

This study reviewed existing antimalarial drugs and resistance–associated variants contributing to the diminished sensitivity of antimalarials, especially chloroquine, sulfadoxine-pyrimethamine and artemisinin combination therapy within the African population. It also described various computational techniques implemented in predicting drug targets and leads in drug research. In the data analysis, it was showed that possible mechanisms of resistance to artemisinin in Africa may arise from the combinatorial effects of many resistant genes to chloroquine and sulfadoxine–pyrimethamine. The role of pfk13 within the host–pathogen network was investigated and it also predicted key targets that have been proposed to be essential for malaria drug and vaccine development through structural and functional analysis of host and pathogen function networks. Based on the analysis, these targets are proposed to be as essential co-targets for combinatorial malaria drug discovery.

This project leveraged malaria-specific genome wide association study summary statistics data obtained from Gambia, Kenya and Malawi populations, Plasmodium falciparum selective pressure variants and functional datasets (protein sequences, interologs, host-pathogen intra-organism and host-pathogen inter-organism protein-protein interactions (PPIs)) from various sources (STRING, Reactome, HPID, Uniprot, IntAct and literature) to construct overlapping functional network for both host and pathogen. Developed algorithms and a large-scale data-driven computational framework were used in this study to analyze the datasets and the constructed networks to identify densely connected subnetworks or hubs essential for network stability and integrity. The host-pathogen network was analyzed to elucidate the influence of parasite candidate key proteins within the network and predict possible resistant pathways due to host-pathogen candidate key protein interactions. Biological and pathway enrichment analysis were performed on critical proteins identified to elucidate their functions. In order to leverage disease-target-drug relationships to identify potential repurposable already approved drug candidates that could be used to treat malaria, pharmaceutical datasets from drug bank were explored using semantic similarity approach based of target–associated biological processes.

Project details

Genetics and Genomics

Sep 2020

South Africa