Cellular networks involved in the influenza virus life cycle

Abstract

Influenza viruses cause epidemics and pandemics. Like all viruses, influenza viruses rely on the host cellular machinery to support their life cycle. Accordingly, identification of the host functions co-opted for viral replication is of interest to understand the mechanisms of the virus life cycle and to find new targets for the development of antiviral compounds. Among the various approaches used to explore host factor involvement in the influenza virus replication cycle, perhaps the most powerful is RNAi-based genome-wide screening, which has shed new light on the search for host factors involved in virus replication. In this review, we examine the cellular genes identified to date as important for influenza virus replication in genome-wide screens, assess pathways that were repeatedly identified in these studies, and discuss how these pathways might be involved in the individual steps of influenza virus replication, ultimately leading to a comprehensive understanding of the virus life cycle.

Figure 1. Influenza virus life cycle and host factors

Upon infection, influenza virus is internalized by receptor-mediated endocytosis. After membrane fusion between the virus envelope and the endosome, the viral ribonucleoprotein (vRNP) complex is released into the cytoplasm and transported into the nucleus by the active import machinery of the host cell nuclear pore complex. Replication and transcription of the viral genome take place in the nucleus and many host factors are believed to be involved in this process. Newly synthesized viral RNA associates with NP and forms the viral ribonucleoprotein (vRNP) complex together with viral polymerase proteins, which is then transported from the nucleus to the cytoplasm. HA and NA are processed posttranslationally during their transport from the ER to the Golgi apparatus. During assembly and budding, virion components are transported to the assembly site, the lipid raft microdomains at the apical plasma membrane of polarized epithelial cells. Progeny viruses then bud from the cells. The light orange rectangles indicate individual steps of the influenza virus life cycle. The light blue rectangles indicate host cellular processes that may be involved in the virus life cycle. Red circles indicate host factors identified in the screens discussed here, while yellow circles indicate host factors identified in other previous studies.

Figure 2. A network of host-influenza virus interactions

Using GeneGo (GeneGo Inc, MI, USA), we analyzed the interactions of the 128 human genes identified to be involved in influenza virus replication in at least two genome-wide screens (Supplementary Table S4A). We then integrated this information with data on host protein-virus interactions and interactions among viral proteins, as reported by Konig et al. (2010) and Shapira et al. (2009) (Supplementary Table S4B). Interaction networks among host and viral proteins (i.e., PA, PB1, PB2, NP, HA, NA, M1, M2, NS1, NEP/NS2, and PB1-F2)(Fig 2A), virions (Fig 2B), or vRNP (Fig 2C) were visualized by using Cytoscape (http://cytoscape.org/). Yellow and lilac nodes indicate influenza viral components and host proteins, respectively. Red circles indicate clusters associated with particular biological processes in the interaction networks, as identified by MCODE (“Molecular Complex Detection”) analysis (Bader and Hogue, 2003): 1) translation initiation, 2) pre-mRNA processing, and 3) proton-transporting V-type ATPase.

Figure 2. A network of host-influenza virus interactions

Using GeneGo (GeneGo Inc, MI, USA), we analyzed the interactions of the 128 human genes identified to be involved in influenza virus replication in at least two genome-wide screens (Supplementary Table S4A). We then integrated this information with data on host protein-virus interactions and interactions among viral proteins, as reported by Konig et al. (2010) and Shapira et al. (2009) (Supplementary Table S4B). Interaction networks among host and viral proteins (i.e., PA, PB1, PB2, NP, HA, NA, M1, M2, NS1, NEP/NS2, and PB1-F2)(Fig 2A), virions (Fig 2B), or vRNP (Fig 2C) were visualized by using Cytoscape (http://cytoscape.org/). Yellow and lilac nodes indicate influenza viral components and host proteins, respectively. Red circles indicate clusters associated with particular biological processes in the interaction networks, as identified by MCODE (“Molecular Complex Detection”) analysis (Bader and Hogue, 2003): 1) translation initiation, 2) pre-mRNA processing, and 3) proton-transporting V-type ATPase.

Figure 2. A network of host-influenza virus interactions

Using GeneGo (GeneGo Inc, MI, USA), we analyzed the interactions of the 128 human genes identified to be involved in influenza virus replication in at least two genome-wide screens (Supplementary Table S4A). We then integrated this information with data on host protein-virus interactions and interactions among viral proteins, as reported by Konig et al. (2010) and Shapira et al. (2009) (Supplementary Table S4B). Interaction networks among host and viral proteins (i.e., PA, PB1, PB2, NP, HA, NA, M1, M2, NS1, NEP/NS2, and PB1-F2)(Fig 2A), virions (Fig 2B), or vRNP (Fig 2C) were visualized by using Cytoscape (http://cytoscape.org/). Yellow and lilac nodes indicate influenza viral components and host proteins, respectively. Red circles indicate clusters associated with particular biological processes in the interaction networks, as identified by MCODE (“Molecular Complex Detection”) analysis (Bader and Hogue, 2003): 1) translation initiation, 2) pre-mRNA processing, and 3) proton-transporting V-type ATPase.