Identification of Transcriptionally Induced Antiviral Effectors in Drosophila. Gregory Osborn^1*, Jie Xu¹, Ari Yasunaga¹, Ian Lamborn², Beth Gordesky-Gold¹, Sara Cherry¹. 1) Department of Microbiology, University of Pennsylvania, Philadelphia, PA; 2) Department of Immunology, University of Pennsylvania, Philadelphia, PA.

   The innate immune system is characterized by the precise regulation of gene expression programs to restrict pathogens. We recently identified a virally-induced gene expression program that is rapidly activated by diverse viral infections. We found that the transcriptional pausing pathway is antiviral and controls this response, as over half of this gene induction program is genetically-dependent on pausing and has pausing-associated biochemical chromatin features. Transcriptional pausing and this rapidly induced program plays an essential antiviral role in vivo, as NELF and P-TEFb restrict viral replication in adult flies and in vector mosquito cells. Furthermore, this program included components of all known antiviral pathways including RNA silencing, autophagy, JAK/STAT, Toll, and Imd signaling along with a subset of Toll receptors. This suggests that additional genes within this gene set may have antiviral effector function. Utilizing a directed RNAi screen to these transcriptionally induced genes, we have identified a subset with previously unknown roles in Drosophila immunity against multiple viruses.