Tang, Jessica (Juanjie)Innate immunity is essential for the host to defend against invading pathogens, such as viruses and bacteria. To identify novel genes or molecules that are involved in innate immunity, we carried out two genetic screens in <italic>Drosophila</italic>. From a forward screen of flies mutagenized with Ethyl methane sulfonate (EMS), four mutants with increased susceptibility to <italic>Drosophila</italic> X virus (DXV) were found. In this study, we focused on the <italic>rogue</italic> mutant and identified a novel antiviral gene <italic>rogue</italic>. The <italic>rogue</italic> mutant is highly susceptible to DXV infection and is unable to control viral replication during infection. The expression of <italic>rogue</italic> in either the hemocytes or the fat body is required for flies to control viral accumulation and to survive a viral infection. At an early stage of infection, <italic>rogue</italic> is induced and the amount of Rogue protein that locates to the nucleus increases. In addition, we confirm that the Rogue protein interacts with the polyA binding protein (PABP), and we propose that <italic>rogue</italic> restricts viral replication via translation regulation in <italic>Drosophila</italic>. The <italic>rogue</italic> mutant also has a phagosome maturation defect, which may contribute to its susceptibility to <italic>Staphylococcus aureus</italic> infection. RNAi knockdown of <italic>rogue</italic> in the fat body or the hemocytes in wild type flies results in high bacterial susceptibility. Introducing the <italic>rogue</italic> transgene in the hemocytes of the <italic>rogue</italic> mutant can rescue the mutant survival to both DXV and <italic>S. aureus</italic>. Together, our results demonstrate that <italic>rogue</italic> plays a critical role in defending against DXV and <italic>S. aureus</italic> infections. We performed another genetic screen on wild derived inbred flies from the <italic>Drosophila</italic> Genetic Reference Panel (DGRP). From a genome wide association study (GWAS) in these flies, we found four single nucleotide polymorphisms (SNPs) associated with susceptibility of flies to DXV. One allele contributed most to the susceptibility is located in the intron of <italic>Socs36E</italic>, a negative regulator of the JAK-STAT pathway, implicating that the JAK-STAT pathway plays a role in the immune responses against DXV. Our study also shows that natural genetic variation can be used as a tool for identifying novel genes or pathways involved in antiviral immunity.enDissertationGeneticsImmunologyVirologyantiviral responseDrosophila X virusGWASinnate immunityRogue