Epstein-Barr Virus: Human Interactome Reveals New Molecular Insights into Viral Pathogenesis for Potential Therapeutics and Antiviral Drug Discovery.

Host-virus Protein-Protein Interactions (PPIs) play pivotal roles in biological processes crucial for viral pathogenesis and by extension, inform antiviral drug discovery and therapeutics innovations. Despite efforts to develop the Epstein-Barr virus (EBV)-host PPI network, there remain significant knowledge gaps and a limited number of interacting human proteins deciphered. Furthermore, understanding the dynamics of the EBV-host PPI network in the distinct lytic and latent viral stages remains elusive. In this study, we report a comprehensive map of the EBV-human protein interactions, encompassing 1752 human and 61 EBV proteins by integrating data from the public repository HPIDB (v3.0) as well as curated high-throughput proteomic data from the literature. To address the stage-specific nature of EBV infection, we generated two detailed subset networks representing the latent and lytic stages, comprising 747 and 481 human proteins, respectively. Functional and pathway enrichment analysis of these subsets uncovered the profound impact of EBV proteins on cancer. The identification of highly connected proteins and the characterization of intrinsically disordered and cancer-related proteins provide valuable insights into potential therapeutic targets. Moreover, the exploration of drug-protein interactions revealed notable associations between hub proteins and anticancer drugs, offering novel perspectives for controlling EBV pathogenesis. This study represents, to the best of our knowledge, the first comprehensive investigation of the two distinct stages of EBV infection using high-throughput datasets. This makes a contribution to our understanding of EBV-host interactions and provides a foundation for future drug discovery and therapeutic interventions.

Integrative Placental Multi-Omics Analysis Reveals Perturbed Pathways and Potential Prognostic Biomarkers in Gestational Hypertension.

BACKGROUND: Gestational hypertension (GH) is a severe complication that occurs after 20 weeks of pregnancy; however, its molecular mechanisms are not yet fully understood. OBJECTIVE: Through this case-control discovery phase study, we aimed to find disease-specific candidate placental microRNAs (miRNAs) and metabolite markers for differentiating GH by integrating next-generation sequencing and metabolomics multi-omics analysis of placenta. Using small RNA sequencing and metabolomics of placental tissues of healthy pregnant (HP, n = 24) and GH subjects (n = 20), the transcriptome and metabolome were characterized in both groups. RESULTS: The study identified a total of 44 downregulated placental miRNAs which includes three novel, three mature and 38 precursor miRNAs. Six miRNAs including three mature (hsa-miR-181a-5p, hsa-miR-498-5p, and hsa-miR-26b-5p) and three novel (NC_000016.10_1061, NC_000005.10_475, and NC_000001.11_53) were considered for final target prediction and functional annotation. Integrative analysis of differentially expressed miRNAs and metabolites yielded five pathways such as purine, glutathione, glycerophospholipid, inositol phosphate and ß-alanine to be significantly perturbed in GH. We present fourteen genes (LPCAT1, LPCAT2, DGKH, PISD, GPAT2, PTEN, SACM1L, PGM2, AMPD3, AK7, AK3, CNDP1, IDH2, and ODC1) and eight metabolites (xanthosine, xanthine, spermine, glycine, CDP-Choline, glyceraldehyde 3-phosphate, ß-alanine, and histidine) with potential to distinguish GH and HP. CONCLUSION: The differential expression of miRNAs, their target genes, altered metabolites and metabolic pathways in GH patients were identified for the first time in our study. Further, the altered miRNAs and metabolites were integrated to build their inter-connectivity network. The findings obtained from our study may be used as a valuable source to further unravel the molecular pathways associated with GH and also for the evaluation of prognostic markers.

Hepatitis B Virus Modulated Transcriptional Regulatory Map of Hepatic Cellular MicroRNAs.

Hepatitis B virus (HBV) is an enveloped, hepatotropic, noncytopathic virus with a partially double-stranded DNA genome. It infects hepatocytes and is associated with progression to liver fibrosis and cirrhosis, culminating in hepatocellular carcinoma (HCC), accounting for 55% of total HCC cases. MicroRNAs (miRNAs) regulated by HBV play an important role in these pathologies. Mapping the miRNAs responsive to HBV and HBV-specific proteins, including HBV X protein (HBx) that harbor the majority of HBV-human protein interactions, could aid accelerate the diagnostics and therapeutics innovation against the infection and associated diseases. With this in mind, we used a unique annotation strategy whereby we first amassed 362 mature HBV responsive-human Differentially Expressed miRNAs (HBV-hDEmiRs). The core experimentally-validated messenger RNA targets of the HBV-hDEmiRs were mostly associated with viral infections and hepatic inflammation processes. Moreover, our annotation strategy enabled the characterization of HBx-dependent/independent HBV-hDEmiRs as a tool for evaluation of the impact of HBx as a therapeutic target. Bioinformatics analysis of the HBV-human protein-protein interactome revealed new insights into the transcriptional regulatory network of the HBV-hDEmiRs. We performed a comparative analysis of data on miRNAs gathered from HBV infected cell line studies and from tissue studies of fibrosis, cirrhosis, and HCC. Accordingly, we propose hsa-miR-15a-5p that is downregulated by multiple HBV proteins, including HBx, as a potential biomarker of HBV infection, and its progression to HCC. In all, this study underscores (1) the complexity of miRNA regulation in response to HBV infection and its progression into other liver pathologies and (2) provides a regulatory map of HBV-hDEmiRs and the underlying mechanisms modulating their expression through a cross talk between HBV viral proteins and human transcription factors.

VirhostlncR: A comprehensive database to explore lncRNAs and their targets in viral infections.

Long non-coding-RNAs (lncRNAs) are an expanding set of cis-/trans-regulatory RNA genes that outnumber the protein-coding genes. Although being increasingly discovered, the functional role of the majority of lncRNAs in diverse biological conditions is undefined. Increasing evidence supports the critical role of lncRNAs in the emergence, regulation, and progression of various viral infections including influenza, hepatitis, coronavirus, and human immunodeficiency virus. Hence, the identification of signature lncRNAs would facilitate focused analysis of their functional roles accounting for their targets and regulatory mechanisms associated with infections. Towards this, we compiled 2803 lncRNAs identified to be modulated by 33 viral strains in various mammalian cell types and are provided through the resource named VirhostlncR (http://ciods.in/VirhostlncR/). The information on each of the viral strains, their multiplicity of infection, duration of infection, host cell name and cell types, fold change of lncRNA expression, and their specific identification methods are integrated into VirhostlncR. Based on the current datasets, we report 150 lncRNAs including differentiation antagonizing non-protein coding RNA (DANCR), metastasis-associated lung adenocarcinoma transcript 1 (MALAT1), maternally expressed gene 3 (MEG3), nuclear paraspeckle assembly transcript 1 (NEAT1), and plasmacytoma variant translocation 1 (PVT1) to be perturbed by two or more viruses. Analysis of viral protein interactions with human transcription factors (TFs) or TF-containing protein complexes identified that distinct viruses can transcriptionally regulate many of these lncRNAs through multiple protein complexes. Together, we believe that the current dataset will enable priority selection of lncRNAs for identification of their targets and serve as an effective platform for the analysis of noncoding RNA-mediated regulations in viral infections.

A network map of GDNF/RET signaling pathway in physiological and pathological conditions.

Glial cell line-derived neurotrophic factor (GDNF) signals through a multi-component receptor system predominantly consisting of glycosyl-phosphatidylinositol-anchored GDNF family receptor alpha-1 (GFRα1) and the Rearranged during transfection (RET) receptor tyrosine kinase. GDNF/RET signaling is vital to the central and peripheral nervous system, kidney morphogenesis, and spermatogenesis. In addition, the dysregulation of the GDNF/RET signaling has been implicated in the pathogenesis of cancers. Despite the extensive research on GDNF/RET signaling, a molecular network of reactions induced by GDNF reported across the published literature. However, a comprehensive GDNF/RET pathway resource is currently unavailable. We describe an integrated signaling pathway reaction map of GDNF/RET consisting of 1151 molecular reactions. These include information pertaining to 52 molecular association events, 70 enzyme catalysis events, 36 activation/inhibition events, 22 translocation events, 856 gene regulation events, and 115 protein-level expression events induced by GDNF in diverse cell types. We developed a comprehensive GDNF/RET signaling network map based on these molecular reactions. The pathway map was made accessible through WikiPathways database ( https://www.wikipathways.org/index.php/Pathway:WP5143 ). Biocuration and development of gene regulatory network map of GDNF/RET signaling pathway.

Helicobacter pylori regulated microRNA map of human gastric cells.

BACKGROUND: Helicobacter pylori is an infection of concern for its chronic colonization leading to peptic ulcers and gastric cancer. In recent times, microRNAs have been extensively studied to understand their role in the pathogenesis of this bacteria in diverse contexts of gastric diseases. The current analysis reports the microRNA-mRNA interactions that are associated with effective survival and virulence of this pathogen. MATERIALS AND METHODS: We convened differentially regulated human microRNAs responsive to H. pylori infection (HP-hDEmiRs) at different multiplicity of infection and time points in human gastric cell lines through retrospective data mining of experimental studies. In view of the molecular disparity of clinical samples and animal models, data from tissue, serum/plasma, urine, and ascites were excluded. Further, we utilized diverse bioinformatics approaches to retrieve experimentally validated, high-confidence targets of the HP-hDEmiRs to analyze the microRNA-mRNA interactions that are relevant to H. pylori pathogenesis. RESULTS: A total of 39 HP-hDEmiRs that showed unidirectional expression of either overexpression or downregulation were identified to modulate 23 targets explicitly studied under this infection. We also identified 476 experimentally validated targets regulated by at least 4 of the HP-hDEmiRs. In addition to the pathways prior-associated with H. pylori infection, the microRNA-mRNA interactome analysis identified several cellular processes and pathways highly associated with cell cycle, cell division, migration, and carcinogenesis. CONCLUSION: This study generated a platform to study the mechanisms utilized by this pathogen using microRNAs as surrogate.