The Cellular Actin Network and Virus Replication

Viruses dramatically reorganize the infected cells to support viral replication. Since the actin network is a key element in cell organization and transport of cellular proteins, lipids and intracellular organelles, viruses might target the actin network to reprogram cellular pathways and aid assembly of the viral replicase. Accordingly, the exciting discovery that an RNA virus targets cofilin (Cof1), a major regulator of the actin network, opens up the possibility that the actin network could play a critical role in virus-host interactions. The PI finds in high throughput screens that inactivation of the host cofilin gene, which is involved in actin depolymarization and its mutations cause many human diseases, facilitates robust RNA virus replication. The data suggest that an RNA virus actively inhibits the function of cofilin in order to debilitate the function of the actin network in host cells. Altogether, exploring the roles of cofilin and actin in virus infection will facilitate the development of novel antiviral approaches. Progress in our understanding of the mechanisms of host factors is slow due to functional redundancy or lack of knowledge about their functions. However, easily tractable virus - host systems, such as Tomato bushy stunt virus (TBSV) and yeast as a model host can contribute to our understanding of the functions of these host proteins. This project will likely advance our understanding of the role of host cofilin and actin in virus-host interactions. This advance could immensely help other scientists working with less tractable, but devastating viral pathogens for which similar studies are currently not yet feasible. The gained knowledge will likely be useful to invite attention to the deleterious effect of an RNA virus on the actin network. The following are the major strengths of the proposal: (i) Viral RNA replication is clearly of immense importance for viruses to infect living organisms. (ii) Cofilin and actin are major proteins affecting human diseases, yet their roles in virus replication are currently poorly defined. (iii) The combination of yeast and authentic cell-free assay developed by the PI is currently the most potent for studying the mechanism of host factors involvement in viral RNA replication and viral pathogenesis. (iv) The research holds promise of benefiting society by leading to groundbreaking results in the area of virus replication, host-virus interactions and the adaptation of viruses to their hosts.