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

Background: 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 drugresistant 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. Objective: The overall objective of this study is to identify potential protein targets through host–pathogen protein–protein functional interaction network analysis to understand the underlying mechanisms of drug failure and identify those essential targets that can play their role in predicting potential drug candidates specific to the African populations through a protein-based approach of both host and Plasmodium falciparum genomic analysis. Methods: We 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. We performed biological and pathway enrichment analysis 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 Results: About 600,000 significant SNPs (p-value< 0.05) from the summary statistics data were mapped to their associated genes, and we identified 79 human-associated malaria genes. 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. We also explored the association of pfk13 gene within the host-pathogen. We 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. We implemented semantic similarity based approach 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. Conclusion: In this study, we 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. We also described various computational techniques implemented in predicting drug targets and leads in drug research. In our data analysis, we 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. We investigated the role of pfk13 within the host–pathogen network. We 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 our analysis, we propose these targets as essential co-targets for combinatorial malaria drug discovery

Recent trends in molecular diagnostics of yeast infections : from PCR to NGS

The incidence of opportunistic yeast infections in humans has been increasing over recent years. These infections are difficult to treat and diagnose, in part due to the large number and broad diversity of species that can underlie the infection. In addition, resistance to one or several antifungal drugs in infecting strains is increasingly being reported, severely limiting therapeutic options and showcasing the need for rapid detection of the infecting agent and its drug susceptibility profile. Current methods for species and resistance identification lack satisfactory sensitivity and specificity, and often require prior culturing of the infecting agent, which delays diagnosis. Recently developed high-throughput technologies such as next generation sequencing or proteomics are opening completely new avenues for more sensitive, accurate and fast diagnosis of yeast pathogens. These approaches are the focus of intensive research, but translation into the clinics requires overcoming important challenges. In this review, we provide an overview of existing and recently emerged approaches that can be used in the identification of yeast pathogens and their drug resistance profiles. Throughout the text we highlight the advantages and disadvantages of each methodology and discuss the most promising developments in their path from bench to bedside

Named Entity Recognition for Bacterial Type IV Secretion Systems

Research on specialized biological systems is often hampered by a lack of consistent terminology, especially across species. In bacterial Type IV secretion systems genes within one set of orthologs may have over a dozen different names. Classifying research publications based on biological processes, cellular components, molecular functions, and microorganism species should improve the precision and recall of literature searches allowing researchers to keep up with the exponentially growing literature, through resources such as the Pathosystems Resource Integration Center (PATRIC, patricbrc.org). We developed named entity recognition (NER) tools for four entities related to Type IV secretion systems: 1) bacteria names, 2) biological processes, 3) molecular functions, and 4) cellular components. These four entities are important to pathogenesis and virulence research but have received less attention than other entities, e.g., genes and proteins. Based on an annotated corpus, large domain terminological resources, and machine learning techniques, we developed recognizers for these entities. High accuracy rates (>80%) are achieved for bacteria, biological processes, and molecular function. Contrastive experiments highlighted the effectiveness of alternate recognition strategies; results of term extraction on contrasting document sets demonstrated the utility of these classes for identifying T4SS-related documents

High-throughput and computational approaches for diagnostic and prognostic host tuberculosis biomarkers

High-throughput techniques strive to identify new biomarkers that will be useful for the diagnosis, treatment, and prevention of tuberculosis (TB). However, their analysis and interpretation pose considerable challenges. Recent developments in the high-throughput detection of host biomarkers in TB are reported in this review

Computational health engineering applied to model infectious diseases and antimicrobial resistance spread

Infectious diseases are the primary cause of mortality worldwide. The dangers of infectious disease are compounded with antimicrobial resistance, which remains the greatest concern for human health. Although novel approaches are under investigation, the World Health Organization predicts that by 2050, septicaemia caused by antimicrobial resistant bacteria could result in 10 million deaths per year. One of the main challenges in medical microbiology is to develop novel experimental approaches, which enable a better understanding of bacterial infections and antimicrobial resistance. After the introduction of whole genome sequencing, there was a great improvement in bacterial detection and identification, which also enabled the characterization of virulence factors and antimicrobial resistance genes. Today, the use of in silico experiments jointly with computational and machine learning offer an in depth understanding of systems biology, allowing us to use this knowledge for the prevention, prediction, and control of infectious disease. Herein, the aim of this review is to discuss the latest advances in human health engineering and their applicability in the control of infectious diseases. An in-depth knowledge of host?pathogen?protein interactions, combined with a better understanding of a host?s immune response and bacterial fitness, are key determinants for halting infectious diseases and antimicrobial resistance dissemination

An explainable model of host genetic interactions linked to COVID-19 severity

We employed a multifaceted computational strategy to identify the genetic factors contributing to increased risk of severe COVID-19 infection from a Whole Exome Sequencing (WES) dataset of a cohort of 2000 Italian patients. We coupled a stratified k-fold screening, to rank variants more associated with severity, with the training of multiple supervised classifiers, to predict severity based on screened features. Feature importance analysis from tree-based models allowed us to identify 16 variants with the highest support which, together with age and gender covariates, were found to be most predictive of COVID-19 severity. When tested on a follow-up cohort, our ensemble of models predicted severity with high accuracy (ACC = 81.88%; AUCROC = 96%; MCC = 61.55%). Our model recapitulated a vast literature of emerging molecular mechanisms and genetic factors linked to COVID-19 response and extends previous landmark Genome-Wide Association Studies (GWAS). It revealed a network of interplaying genetic signatures converging on established immune system and inflammatory processes linked to viral infection response. It also identified additional processes cross-talking with immune pathways, such as GPCR signaling, which might offer additional opportunities for therapeutic intervention and patient stratification. Publicly available PheWAS datasets revealed that several variants were significantly associated with phenotypic traits such as "Respiratory or thoracic disease", supporting their link with COVID-19 severity outcome.A multifaceted computational strategy identifies 16 genetic variants contributing to increased risk of severe COVID-19 infection from a Whole Exome Sequencing dataset of a cohort of Italian patients

An explainable model of host genetic interactions linked to COVID-19 severity

We employed a multifaceted computational strategy to identify the genetic factors contributing to increased risk of severe COVID-19 infection from a Whole Exome Sequencing (WES) dataset of a cohort of 2000 Italian patients. We coupled a stratified k-fold screening, to rank variants more associated with severity, with the training of multiple supervised classifiers, to predict severity based on screened features. Feature importance analysis from tree-based models allowed us to identify 16 variants with the highest support which, together with age and gender covariates, were found to be most predictive of COVID-19 severity. When tested on a follow-up cohort, our ensemble of models predicted severity with high accuracy (ACC = 81.88%; AUCROC = 96%; MCC = 61.55%). Our model recapitulated a vast literature of emerging molecular mechanisms and genetic factors linked to COVID-19 response and extends previous landmark Genome-Wide Association Studies (GWAS). It revealed a network of interplaying genetic signatures converging on established immune system and inflammatory processes linked to viral infection response. It also identified additional processes cross-talking with immune pathways, such as GPCR signaling, which might offer additional opportunities for therapeutic intervention and patient stratification. Publicly available PheWAS datasets revealed that several variants were significantly associated with phenotypic traits such as “Respiratory or thoracic disease”, supporting their link with COVID-19 severity outcome

Bioinformatics in translational drug discovery

Bioinformatics approaches are becoming ever more essential in translational drug discovery both in academia and within the pharmaceutical industry. Computational exploitation of the increasing volumes of data generated during all phases of drug discovery is enabling key challenges of the process to be addressed. Here, we highlight some of the areas in which bioinformatics resources and methods are being developed to support the drug discovery pipeline. These include the creation of large data warehouses, bioinformatics algorithms to analyse ‘big data’ that identify novel drug targets and/or biomarkers, programs to assess the tractability of targets, and prediction of repositioning opportunities that use licensed drugs to treat additional indications

Designing Data-Driven Learning Algorithms: A Necessity to Ensure Effective Post-Genomic Medicine and Biomedical Research

Advances in sequencing technology have significantly contributed to shaping the area of genetics and enabled the identification of genetic variants associated with complex traits through genome-wide association studies. This has provided insights into genetic medicine, in which case, genetic factors influence variability in disease and treatment outcomes. On the other side, the missing or hidden heritability has suggested that the host quality of life and other environmental factors may also influence differences in disease risk and drug/treatment responses in genomic medicine, and orient biomedical research, even though this may be highly constrained by genetic capabilities. It is expected that combining these different factors can yield a paradigm-shift of personalized medicine and lead to a more effective medical treatment. With existing “big data” initiatives and high-performance computing infrastructures, there is a need for data-driven learning algorithms and models that enable the selection and prioritization of relevant genetic variants (post-genomic medicine) and trigger effective translation into clinical practice. In this chapter, we survey and discuss existing machine learning algorithms and post-genomic analysis models supporting the process of identifying valuable markers