The objective of this project is to analyze host defense mechanisms against viral infection in the model[unreadable] organism Drosophila melanogaster, and to do so in the light of concurrent studies of viral infection in mice,[unreadable] carried out by our colleagues in La Jolla and in Osaka. Like all other organisms, insects are afflicted by[unreadable] viruses and react to viral infections. We posit that by studying the response of Drosophila to viral infection we[unreadable] will uncover evolutionary conserved mechanisms of innate immunity that, together with the programs[unreadable] developed in the other participating laboratories, will help to unravel the essential aspects of the antiviral[unreadable] response in mammals. The project has three specific aims. The first two aims are based on our studies of[unreadable] the global transcriptional response to infection by two RNA viruses. The genes induced by virus infection will[unreadable] be used as markers in forward genetic screens to identify mutations that impair the antiviral response[unreadable] (Specific Aim 1). Moreover, interesting candidate antiviral effector molecules will be selected from the list of[unreadable] genes induced by viral infection, and functionally characterized (Specific Aim 2). The third aim is to provide[unreadable] an extended view of the complete repertoire of responses to virus infection in Drosophila, using microarrays[unreadable] to compare the response to infection in different tissues, to investigate the response to different types of[unreadable] viruses (in particular DMA viruses), and finally, to analyze the response to viral RNA and viral proteins. The[unreadable] relevance of this research to public health will be three-fold. First, characterization of the pristine host[unreadable] defense against viral infection in Drosophila may reveal novel evolutionary conserved pathways of host[unreadable] defense in mammals, as occurred in the case of Toll-like receptors. Second, the Drosophila model may[unreadable] reveal original strategies to counter viral infection that may guide the development of antiviral therapeutics.[unreadable] Third, emerging viral diseases with global impact, such as West Nile virus infection, are transmitted by[unreadable] Aedes mosquitoes, which, like Drosophila, belong to the order Diptera. Our research may shed light on the[unreadable] interaction between arthropod-borne viruses and their insect vectors.