PROJECT SUMMARY The elderly proportion of the human population is increasing rapidly on a global scale leading to unprecedented demographic shift impacting families, governments and health care systems. In addition to being at higher risk for developing chronic disease, older individuals are more vulnerable than younger adults to infectious diseases, including viral infections, and often exhibit higher incidence, severity and mortality rates. Moreover, the aged organism represents a favorable environment for the accumulation of mutations in viral genomes that could possibly result in the emergence of novel pathogenic strains of significant public health concern. The exact mechanisms leading to that, however, are not known. Despite numerous advances in understanding virus-host interactions, we do not know if differential processes underlie these relationships as a function of age. With ever- increasing numbers of older persons on the planet, appropriate preventive and treatment strategies leading to a longer, healthier life are becoming increasingly urgent. Consequently, there is great need to unravel the fundamental mechanisms that allow the aged organism to survive infection and limit pathogen spread. Here, we propose to use the model organism Drosophila melanogaster to identify the mechanisms that contribute to age-dependent survival of infection with the RNA Flock House Virus (FHV) and the influence of the aged organism on viral pathogenicity. The host and the virus reciprocally affect each other and we will examine both how the aged host responds to, and conversely affects, the virus. We propose to use an innovative combination of genetic, molecular, metabolic and next generation sequencing methods to: (1) determine how modulation of host’s metabolism in older individuals aids in survival of viral infection and (2) determine how the aged organism’s physiological milieu impacts the evolution of RNA virus pathogenicity. Our experiments will focus on investigating the role of infection tolerance mechanisms that rely on the modulation of organismal metabolism as an age-dependent strategy to survive infection. To determine how the aged host’s physiological environment potentiates RNA virus pathogenicity, we will examine the architecture of viral genomes, including the build up of defective viral species, following replication in older versus younger individuals, and over several passages in vivo. We will also test the contribution of increased oxidative stress in this process using both genetic and pharmacological approaches, and perform pathogenicity studies using identified candidate viral variants. The underlying genetic and molecular mechanisms are likely to be conserved from flies to humans and our studies will provide important new insights filling the knowledge gap about the interactions of viruses and aged hosts in general. Our studies could potentially lead to therapeutic improvements for infected elderly patients as well as to the preve...