Viruses.STRING: A Virus-Host Protein-Protein Interaction Database

Abstract

As viruses continue to pose risks to global health, having a better understanding of virus⁻host protein⁻protein interactions aids in the development of treatments and vaccines. Here, we introduce Viruses.STRING, a protein⁻protein interaction database specifically catering to virus⁻virus and virus⁻host interactions. This database combines evidence from experimental and text-mining channels to provide combined probabilities for interactions between viral and host proteins. The database contains 177,425 interactions between 239 viruses and 319 hosts. The database is publicly available at viruses.string-db.org, and the interaction data can also be accessed through the latest version of the Cytoscape STRING app.

Keywords: PPI database; protein–protein interactions; virus bioinformatics; virus–host interactions.

Figure 1

Orthologous relationship transfer in Viruses.STRING. STRING intra-species interactions are transferred between organisms as shown in (a): an interaction between two proteins in species 1 (solid thick line) is transferred to two orthologous proteins in species 2 (dashed line). Orthologous relationships are indicated by solid thin lines. This relationship is identical to transferring an interaction between two virus proteins of one virus species to two orthologous proteins in another virus species. Cross species interactions are handled as one of three cases—same host to closely related virus (b), the same virus to closely related host (c), or both a new host and new virus at the same time (d). Note that we transfer only to already known virus–host pairs and that we are not predicting new virus–host relationships via orthology transfer; (e) shows the evolutionary history of a gene that underwent a gene duplication event after the last common ancestor of Chordata, but prior to the last common ancestor of mammals. There was subsequently a speciation event that resulted in the duplicated gene being present in both human and mouse. Orthology groups can be read by following the lines up the tree—at the level of Mammalia, the light and dark genes are in separate orthology groups, but at higher levels, they are in the same orthology group.

Figure 2

Intra- and intervirus interactions in viruses.STRING by species. (A) distribution of experimental (red) and text mining (green) interactions present in the database, further divided into direct (dark red and dark green) and transferred (light green and pink) evidence. Data is shown for the 20 viruses with the most evidence. Evidence may be between two proteins of one virus species, or between a virus protein and a host protein. Evidence is counted as interaction pairs per channel, such that an interaction that is supported by three channels will be counted as 3 evidences. The sources of evidence that is transferred may originate from experimental (abbreviated ex in the figure) or from text mining (tm) data; (B) amount of evidence normalized by the number of proteins coded for by that virus.

Figure 3

HIV-1 and Homo sapiens interaction network in viruses.STRING. HIV-1 and Homo sapiens interaction network downloaded as a vector image from viruses.STRING. The type of interaction is indicated by edge colour—green: text mining, red: experiments. Additional edge types can be found between host proteins, and come from the STRING database—yellow orange: pathway databases, light blue: protein homology, dark blue: gene co-occurrence, black: co-expression, light green: gene neighbourhoods, pink: gene fusions (last two not present in figure).

Figure 4

HPV and Homo sapiens interaction network in Cytoscape. Proteins from Human Papillomavirus type 16, and HPV type 1a with their human protein interaction partners. Virus proteins are coloured according to their species (dark red: HPV 16, light red: HPV 1a). The human proteins are coloured in shades of green with darker colours showing a stronger association with the nucleus. The dark halos around human proteins are those that are associated with the GO term for cell cycle. The HPV E6 and E7 proteins are known to interfere with the cell cycle. This analysis shows some of the data exploration and visualization flexibility that is easily possible within Cytoscape.