VirHostNet: a knowledge base for the management and the analysis of proteome-wide virus–host interaction networks

Navratil, Vincent; de Chassey, Benoît; Meyniel, Laurène; Delmotte, Stéphane; Gautier, Christian; André, Patrice; Lotteau, Vincent; Rabourdin-Combe, Chantal

In the infection network, the virus-host interactions occurred between 407 viral proteins and 1012 human proteins, suggesting the strong tendency of viruses to interact with a large number of cellular proteins. In order to characterize cellular functions targeted by the viral machinery, we performed functional enrichment analysis of host proteins interacting with viruses, by using Gene Ontology and KEGG databases and the same methodology described by Zheng and Wang (37) (Supplementary Tables 3 and 4 , respectively). The results showed that viruses interact significantly with a large panel of cellular functions (e.g. cell cycle, apoptosis, cell communication, protein transport) and with canonical signalling pathways (e.g. Jak-Stat, Toll-like Receptor, MAPK, TGF-b, mTOR). The majority of these functions and pathways have already been described to participate in either viral infectious cycle, cellular anti-viral mechanisms or viral associated diseases (38) . Interestingly, analysis of KEGG pathways revealed cellular mechanisms poorly documented in the case of viral infections. One example is focal adhesion, a pathway involved in cell contact with the extracellular matrix and in many other cellular processes including invasion, motility, proliferation and apoptosis (39) . Indeed, on 202 protein members of the focal adhesion pathway, more than 25% (59) were found significantly targeted (exact Fisher test, Benjamini-Hochberg multiple correction test P-value < 0.05) by at least one viral protein in 36 distinct viral taxons. This may suggest the central role of focal adhesion during viral infections and its potential impact on viral induced cancer development that might be associated for instance to the loss of cellular adhesion. Although cellular functions of proteins are far from being completely known and/or annotated in public databases, based on the 'guilty by association' concept the human protein-protein network may serve as a template to complete our understanding on cellular functions perturbed during viral infection. In order to include virusvirus and virus-host interactions in their cellular context, a human-human protein interaction network containing roughly 70 000 non-redundant protein-protein interactions and 10 000 proteins was built from public databases (details on interaction methods distribution are given in Supplementary Figure 1) . Thus, based on roughly 40 000 unique proteins annotated in ENSEMBL, 25% (10 000/ 40 000) are connected within the human protein network. Analysis of the infection network revealed that surprisingly 88% (881/1012) of targeted human proteins interact with at least one cellular protein. Thus, targeted proteins tend to physically interact in the cell and may probably participate in cross-linked functions and pathways. Based on protein neighbourhood or sub-networks, the human protein-protein interaction network may help to elucidate new protein regulators or modular functions associated to viral or cellular anti-viral strategies.