When the human viral infectome and diseasome networks collide: towards a systems biology platform for the aetiology of human diseases

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.

A Physical Interaction Network of Dengue Virus and Human Proteins

“…Topological analyses of the proteins targeted by DENV further supports the hypothesis that viruses have evolved strategies to target nodes of higher connectivity and centrality. As previously observed for human proteins that interacted with EBV, HCV, HIV, and INFV (17,21,22,54,128), human proteins that interacted with DENV proteins had higher average degree and betweenness than those in the HPIN as a whole. Similar patterns were found in a larger scale analysis of more than a hundred host-virus interactomes (128).…”

“…As previously observed for human proteins that interacted with EBV, HCV, HIV, and INFV (17,21,22,54,128), human proteins that interacted with DENV proteins had higher average degree and betweenness than those in the HPIN as a whole. Similar patterns were found in a larger scale analysis of more than a hundred host-virus interactomes (128). However, DENV did not interact with the most highly connected human proteins, but rather those with an intermediate number of partners.…”

“…Network Properties of Human Proteins Implicated in Virus Infections-Preferential targeting of highly connected proteins and proteins with high betweenness may enable viruses to efficiently control the flux of infection-relevant information passing through the host interactome (54,128). Topological analyses of the proteins targeted by DENV further supports the hypothesis that viruses have evolved strategies to target nodes of higher connectivity and centrality.…”

The Prediction and Analysis of Inter- and Intra-Species Protein-Protein Interaction

“…Another analysis on human-viral interaction network also highlighted the mechanisms of non-infectious diseases (Navratil et al, 2011 (Navratil et al, 2010).…”

Protein Networks: Generation, Structural Analysis and Exploitation

“…At cellular level, viruses can be considered hackers, which divert the protein network operations toward an illegitimate scope. Indeed, it has been found by several independent groups that viruses selectively target central proteins, causing large effects on the host protein network (de Chassey B. et al, 2008;Navratil V. et al, 2011;Zou X. et al, 2010). Beside robustness, scale-free protein networks show another interesting feature.…”