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.
Autophagy is a highly-conserved catabolic process 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 seven 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, elongation, 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 users 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 using (multi-)omics datasets (e.g. transcriptomic or proteomic data). The resource is publicly accessible at http://autophagynet.org.
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.
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