Key host factors co-opted to form viral replication organelles

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Viruses with RNA genomes cause major losses in agriculture and pose significant risks to human health. To multiply in their hosts, these viruses subvert host proteins and cellular membranes to build large viral replication organelles that serve to propagate viruses in the infected cells. These intricate organelles are essential for replication, in part by protecting the viral genomes from attack by the host's immune system. Despite the costly agricultural and medical impact of these viruses, the biogenesis of viral replication organelles is incompletely understood. This project employs plant-infecting tombusviruses to address this key component of the viral life cycle. Insights gained from this project include novel strategies to inhibit the formation of the replication organelles, thereby providing methods to block virus replication and facilitate the development of novel, potent and broad-range antiviral approaches. The research will promote interdisciplinary training for graduate students and a postdoctoral researcher across fields that include plant pathology, biochemistry and cell biology. The lab will also provide hands-on research opportunities for high school students. Tomato bushy stunt virus, which is among the most advanced viral systems, will be used to unravel the roles of host factors in replication organelle formation. The emerging picture with many viruses is that the formation of replication organelles, which concentrate viral and host components and provide protection against antiviral responses by the host, absolutely critical for virus replication. A major breakthrough in this area by the PI is the identification of critical co-opted host proteins, namely Sac1 lipid phosphatase, Fis1 mitochondrial fission protein and Atg11 autophagy scaffold protein as key host factors in the biogenesis of tombusvirus replication organelles. These co-opted cellular proteins interact with each other, with the hijacked cellular membranes and with the viral replication proteins and likely serve as key assembly platforms for the biogenesis of replication organelles. The PI will identify their pro-viral functions based on the awesome power of yeast genetics in combination with elegant cell-free replication assays developed for tombusviruses by the PI. Similar work will be extended to TBSV-plant infections, which will likely lead to major new insights into RNA virus replication and viral pathogenesis. Developing an efficient antiviral strategy based on blocking the function of co-opted Sac1, Fis1 or Atg11 could rapidly be done in the elegant tombusvirus-yeast/plant systems. Inhibition of formation of critical viral replication organelles could be a powerful approach to block virus replication, thus the proposed research will facilitate the development of novel, potent and broad-range antiviral approaches.This award reflects NSF's statutory mission and has been deemed worthy of support through evaluation using the Foundation's intellectual merit and broader impacts review criteria.