MicroRNA Guided In Silico Drug Repositioning for Malaria.

BACKGROUND: The rise in Plasmodium resistant strains, decreasing susceptibility to first-line combination therapies, and inadequate efficacy shown by vaccines developed to date necessitate innovative approaches to combat malaria. Drug repurposing refers to finding newer indications for existing medications that provide significant advantages over de novo drug discovery, leading to rapid treatment options. Growing evidence suggests that drugs could regulate the expression of disease-associated microRNAs (miRNAs), implying the potential of miRNAs as attractive targets of therapy for several diseases. METHODS: We aimed to computationally predict drug-disease relationships through miRNAs for the potential repurposing of the drugs as antimalarials. To achieve this, we created a model that combines experimentally validated miRNA-drug interactions and miRNA-disease correlations, assuming that drugs will be linked to disease if they share significant miRNAs. The first step involved constructing a network of drug-drug interactions using curated drug-miRNA relations from the Pharmaco-miR and SM2miR databases. Additionally, the drug-disease relations were acquired from the comparative toxicogenomics database (CTD), and the random walk with restart (RWR) algorithm was applied to the interaction network to anticipate newer drug indications. Further, experimentally verified miRNA-disease associations were procured from the human microRNA disease database (HMDD), followed by an evaluation of the model's performance by examining case studies retrieved from the literature. RESULTS: Topological network analysis revealed that beta-adrenergic drugs in the network that are closely linked may have a tendency to be used as antimalarials. Case studies retrieved from the literature demonstrated acceptable model performance. A few of the predicted drugs, namely, propranolol, metoprolol, epinephrine, and atenolol, have been evaluated for their association with malaria, thereby indicating the adequacy of our model and offering experimental leads for alternative drugs. CONCLUSION: The study puts forth a computational model for forecasting potential connections between beta-adrenergic receptor targeting drugs and malaria to suggest potential for future drug repurposing. This takes into account the concept of commonly associated miRNA partners and providing a mechanistic basis for targeting diseases, elucidating the implication of miRNAs in novel drug-disease relations.

AutophagyNet: high-resolution data source for the analysis of autophagy and its regulation.

Macroautophagy/autophagy is a highly-conserved catabolic procss eliminating dysfunctional cellular components and invading pathogens. Autophagy malfunction contributes to disorders such as cancer, neurodegenerative and inflammatory diseases. Understanding autophagy regulation in health and disease has been the focus of the last decades. We previously provided an integrated database for autophagy research, the Autophagy Regulatory Network (ARN). For the last eight years, this resource has been used by thousands of users. Here, we present a new and upgraded resource, AutophagyNet. It builds on the previous database but contains major improvements to address user feedback and novel needs due to the advancement in omics data availability. AutophagyNet contains updated interaction curation and integration of over 280,000 experimentally verified interactions between core autophagy proteins and their protein, transcriptional and post-transcriptional regulators as well as their potential upstream pathway connections. AutophagyNet provides annotations for each core protein about their role: 1) in different types of autophagy (mitophagy, xenophagy, etc.); 2) in distinct stages of autophagy (initiation, expansion, termination, etc.); 3) with subcellular and tissue-specific localization. These annotations can be used to filter the dataset, providing customizable download options tailored to the user's needs. The resource is available in various file formats (e.g. CSV, BioPAX and PSI-MI), and data can be analyzed and visualized directly in Cytoscape. The multi-layered regulation of autophagy can be analyzed by combining AutophagyNet with tissue- or cell type-specific (multi-)omics datasets (e.g. transcriptomic or proteomic data). The resource is publicly accessible at http://autophagynet.org.Abbreviations: ARN: Autophagy Regulatory Network; ATG: autophagy related; BCR: B cell receptor pathway; BECN1: beclin 1; GABARAP: GABA type A receptor-associated protein; IIP: innate immune pathway; LIR: LC3-interacting region; lncRNA: long non-coding RNA; MAP1LC3B: microtubule associated protein 1 light chain 3 beta; miRNA: microRNA; NHR: nuclear hormone receptor; PTM: post-translational modification; RTK: receptor tyrosine kinase; TCR: T cell receptor; TLR: toll like receptor.

Distinct evolution of type I glutamine synthetase in Plasmodium and its species-specific requirement.

Malaria parasite lacks canonical pathways for amino acid biosynthesis and depends primarily on hemoglobin degradation and extracellular resources for amino acids. Interestingly, a putative gene for glutamine synthetase (GS) is retained despite glutamine being an abundant amino acid in human and mosquito hosts. Here we show Plasmodium GS has evolved as a unique type I enzyme with distinct structural and regulatory properties to adapt to the asexual niche. Methionine sulfoximine (MSO) and phosphinothricin (PPT) inhibit parasite GS activity. GS is localized to the parasite cytosol and abundantly expressed in all the life cycle stages. Parasite GS displays species-specific requirement in Plasmodium falciparum (Pf) having asparagine-rich proteome. Targeting PfGS affects asparagine levels and inhibits protein synthesis through eIF2α phosphorylation leading to parasite death. Exposure of artemisinin-resistant Pf parasites to MSO and PPT inhibits the emergence of viable parasites upon artemisinin treatment.

Erythrocyte miRNA-92a-3p interactions with PfEMP1 as determinants of clinical malaria.

Based on the recently added high throughput analysis data on small noncoding RNAs in modulating disease pathophysiology of malaria, we performed an integrative computational analysis for exploring the role of human-host erythrocytic microRNAs (miRNAs) and their influence on parasite survival and host homeostasis. An in silico analysis was performed on transcriptomic datasets accessed from PlasmoDB and Gene Expression Omnibus (GEO) repositories analyzed using miRanda, miRTarBase, mirDIP, and miRDB to identify the candidate miRNAs that were further subjected to network analysis using MCODE and DAVID. This was followed by immune infiltration analysis and screening for RNA degradation mechanisms. Seven erythrocytic miRNAs, miR-451a, miR-92a-3p, miR-16-5p, miR-142-3p, miR-15b-5p, miR-19b-3p, and miR-223-3p showed favourable interactions with parasite genes expressed during blood stage infection. The miR-92a-3p that targeted the virulence gene PfEMP1 showed drastic reduction during infection. Performing pathway analysis for the human-host gene targets for the miRNA identified TOB1, TOB2, CNOT4, and XRN1 genes that are associated to RNA degradation processes, with the exoribonuclease XRN1, highly enriched in the malarial samples. On evaluating the role of exoribonucleases in miRNA degradation further, the pattern of Plasmodium falciparum_XRN1 showed increased levels during infection thus suggesting a defensive role for parasite survival. This study identifies miR-92a-3p, a member of C13orf25/ miR-17-92 cluster, as a novel miRNA inhibitor of the crucial parasite genes responsible for symptomatic malaria. Evidence for a plausible link to chromosome 13q31.3 loci controlling the epigenetic disease regulation is also suggested.

Therapeutics through glycobiology: an approach for targeted elimination of malaria.

The emergence of drug resistance in Plasmodium jeopardises worldwide malaria eradication efforts necessitating novel therapeutic approaches and therefore the identification of key metabolic pathways of parasite and human host for drug development garners importance. Enzymopathies like glucose-6-phosphate-dehydrogenase (G6PD) and pyruvate kinase (PK) deficiencies have been shown to protect against the severe consequences of malaria. Glycome profiles and the regulatory mechanisms involving the microRNAs or transcription factors' expression related to the histo-blood group glycogenes may add up to resolve the underlying pathogenesis. The glycan derivatives viz. heparin-like molecules (HLMs) interrupt parasite proliferation that can be exploited as leads for alternative therapies. The Plasmodium invasion of erythrocytes involve events of receptor recognition, adhesion, and ligand interactions. Since post translational modifications like N-glycosylation of merozoite surface proteins and several erythrocyte cluster of differentiation (CD) antigens and complement receptor, among others, are crucial to parasite invasion, understanding of post translational modification of proteins involved in the parasite-host interactions should identify viable antimalarial strategies.

Malaria Epidemiology and COVID-19 Pandemic: Are They Interrelated?

Coronavirus disease 2019 (COVID-19) is a systemic disease, impacting multiple organs in the human body. But COVID-19 also impacts other diseases of relevance to public and planetary health. To understand and respond to the COVID-19 pandemic, we need an intersectional conceptual lens and systems thinking. For example, the strain on health care systems due to COVID-19 has adversely impacted global malaria elimination programs. With many epidemiological, clinical, and biological parallels documented, we examined in this study the scenario of malaria and COVID-19 syndemic in India. The disruptive influence of COVID-19 on the National Framework for Malaria Elimination (NFME), impact of unintended chemoprophylaxis, population genetic influences, and the shifting patterns of epidemiology are compared. Importantly, a time series analysis forecasted the burden of malaria increasing in the upcoming years. Although reported malaria cases showed a decline in 2020 compared to the previous years, an increase in cases was documented in 2021, with nine states reporting an increase up to July 2021. Pandemics often cause crosscutting disruptions in health care. Reshaping the priorities of the malaria elimination program and a diligent implementation of the priorities in the NFME would, therefore, be well-advised: (1) vector control, (2) antimalarial therapy recommendations, (3) monitoring drug resistance, (4) prevention of the spread of asymptomatic disease-causing low-density transmission, and (5) large-scale testing measures. In conclusion, the findings from the present study inform future comparative studies in other world regions to better understand the broader, systemic, temporal, and spatial impacts of the COVID-19 pandemic on existing and future diseases across public health systems and services.

Erythrocyte miRNA regulators and malarial pathophysiology.

Pathophysiology of Plasmodium falciparum and Plasmodium vivax in malaria vis a vis host and the parasite genome interactions has been deciphered recently to present the biology of cerebral malaria, severe anaemia and placental malaria. Small non-coding RNAs have exhibited their potential to be considered as indicators and regulators of diseases. The malarial pathologies and their associated mechanisms mediated by miRNAs and their role in haematopoiesis and red cell-related disorders are elucidated. Evidence of miRNA carrying exosome-like vesicles released during infection, delivering signals to endothelial cells enhancing gene expression, resulting in parasite sequestration and complications leading to pathologies of cerebral malaria are important breakthroughs. Pregnancy malaria showed Plasmodium surface antigen promoted erythrocyte sequestration in the placental intervillous space, provoking disease development and assorted complications. Syncytiotrophoblast-derived microparticles during pregnancy and fetus development may predict pathophysiological progression on account of their altered miRNA cargoes in malaria.