A comprehensive map of the influenza A virus replication cycle

Abstract

Background: Influenza is a common infectious disease caused by influenza viruses. Annual epidemics cause severe illnesses, deaths, and economic loss around the world. To better defend against influenza viral infection, it is essential to understand its mechanisms and associated host responses. Many studies have been conducted to elucidate these mechanisms, however, the overall picture remains incompletely understood. A systematic understanding of influenza viral infection in host cells is needed to facilitate the identification of influential host response mechanisms and potential drug targets.

Description: We constructed a comprehensive map of the influenza A virus ('IAV') life cycle ('FluMap') by undertaking a literature-based, manual curation approach. Based on information obtained from publicly available pathway databases, updated with literature-based information and input from expert virologists and immunologists, FluMap is currently composed of 960 factors (i.e., proteins, mRNAs etc.) and 456 reactions, and is annotated with ~500 papers and curation comments. In addition to detailing the type of molecular interactions, isolate/strain specific data are also available. The FluMap was built with the pathway editor CellDesigner in standard SBML (Systems Biology Markup Language) format and visualized as an SBGN (Systems Biology Graphical Notation) diagram. It is also available as a web service (online map) based on the iPathways+ system to enable community discussion by influenza researchers. We also demonstrate computational network analyses to identify targets using the FluMap.

Conclusion: The FluMap is a comprehensive pathway map that can serve as a graphically presented knowledge-base and as a platform to analyze functional interactions between IAV and host factors. Publicly available webtools will allow continuous updating to ensure the most reliable representation of the host-virus interaction network. The FluMap is available at http://www.influenza-x.org/flumap/.

Figure 1

FluMap, a comprehensive IAV pathway map. FluMap was created with CellDesigner version 4.3. A total of 960 factors and 456 reactions were included. The SBML and high-resolution image PDF files are available as Additional Data. When FluMap is opened in CellDesigner, all factors, reactions, and cellular compartments included in the map are listed in the SBML file, and symbols used to build the map are illustrated in the legend of Additional file 3. (See also Additional file 2).

Figure 2

Simplified version of FluMap. To generate a simplified version of FluMap for a high-level overview, we extracted central components and reactions from the FluMap (virus factors (purple), host factors (green), antiviral factors (orange)), focusing on the inhibition (red) or activation (blue) of IAV replication by host factors.

Figure 3

Flowchart of the IAV life cycle. The simplified FluMap (Figure 2) was converted into a linear process flow diagram and separated into the different phases of the viral life cycle (top portion), viral processes (middle portion), and host interaction factors (lower portion). Interactions are classified as inhibitory (red), stimulating (blue), and transition (black). Enclosure in the middle (orange line) indicates nucleoplasm.

Figure 4

Controllability analysis. Critical factors (nodes) identified by the controllability analysis are shown in red. Thick magenta edges indicate critical interactions between viral and host proteins, purple edges indicate virus factor interactions/transitions (for example, transport processes), and orange edges indicate interactions between host factors.