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Abstract
BackgroundComprehensive understanding of molecular mechanisms underlying viral infection is a major challenge towards the discovery of new antiviral drugs and susceptibility factors of human diseases. New advances in the field are expected from systems-level modelling and integration of the incessant torrent of high-throughput "-omics" data.ResultsHere, we describe the Human Infectome protein interaction Network, a novel systems virology model of a virtual virus-infected human cell concerning 110 viruses. This in silico model was applied to comprehensively explore the molecular relationships between viruses and their associated diseases. This was done by merging virus-host and host-host physical protein-protein interactomes with the set of genes essential for viral replication and involved in human genetic diseases. This systems-level approach provides strong evidence that viral proteomes target a wide range of functional and inter-connected modules of proteins as well as highly central and bridging proteins within the human interactome. The high centrality of targeted proteins was correlated to their essentiality for viruses' lifecycle, using functional genomic RNAi data. A stealth-attack of viruses on proteins bridging cellular functions was demonstrated by simulation of cellular network perturbations, a property that could be essential in the molecular aetiology of some human diseases. Networking the Human Infectome and Diseasome unravels the connectivity of viruses to a wide range of diseases and profiled molecular basis of Hepatitis C Virus-induced diseases as well as 38 new candidate genetic predisposition factors involved in type 1 diabetes mellitus.ConclusionsThe Human Infectome and Diseasome Networks described here provide a unique gateway towards the comprehensive modelling and analysis of the systems level properties associated to viral infection as well as candidate genes potentially involved in the molecular aetiology of human diseases.
Highlights
Comprehensive understanding of molecular mechanisms underlying viral infection is a major challenge towards the discovery of new antiviral drugs and susceptibility factors of human diseases
We have previously shown that Hepatitis C Virus (HCV) interacts with highly central and bottleneck proteins in the human interactome and built a network model of molecular pathways that are co-deregulated during chronicity [2]
Bottom-up reconstruction of the Human Infectome Network (HIN) In a systems virology perspective, a virus-infected cell was modelled as an integrated system driven by physical interactions between viral and host cellular proteins the Human Infectome Network (HIN, Figure 1a)
Summary
Comprehensive understanding of molecular mechanisms underlying viral infection is a major challenge towards the discovery of new antiviral drugs and susceptibility factors of human diseases. Improved procedures for RNA interference allow large-scale functional screening and provide a promising source of information to systematically identify host factors essential for the replication and propagation of viruses [3,4,5,6,7]. These functional genomics studies have underlined the importance of high-quality “-omics” datasets and the development of integrative and standardized system for their comprehensive analysis, such as the VirHostNet knowledgebase dedicated to virus-host protein-protein interactions [8]
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