Temporal responses in host-virus interactions

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PROJECT SUMMARY In addition of being at higher risk for developing chronic disease, elderly individuals are more vulnerable than younger adults to infectious diseases, including viral infections, and often exhibit higher incidence, severity and mortality rates. Despite numerous advances in understanding the interactions between viruses and their hosts, we lack knowledge about the processes underlying these relationships as a function of age. With the unprecedented numbers of older individuals on the planet, a major goal is to ensure appropriate preventive and treatment strategies leading to a longer, healthier life. Consequently, there is great need to unravel the fundamental mechanisms that lie beneath the capability of the aged organism to survive infection. In this application, we propose to use the model organism Drosophila melanogaster to investigate the mechanisms that contribute to age-dependent survival of infection with an RNA virus. Precisely, we will use a combination of genetic and molecular approaches to 1) investigate the role inflammatory NF-kB pathways play in immunopathology associated with viral infection at older age 2) conduct functional analysis of a set of evolutionarily conserved genes with no previously reported role in antiviral immunity. Our experiments will focus on studying the role of infection tolerance mechanisms as an age-dependent anti-viral defense strategy. We will also seek to determine how the evolutionarily conserved NF-kB inflammatory pathway and possibly other cellular pathways are implicated in the impaired ability of the older host to survive virus infection. This will be done by examining age-dependent outcomes of infection in several mutants for components of the Drosophila IMD NF- kB pathway and in fly lines in which novel candidate genes are being knocked down or overexpressed. Because the underlying genetic and molecular mechanisms are likely to be conserved from flies to humans, we expect these studies to provide important new insights filling the knowledge gap about the interactions of viruses and their older hosts. Our studies could potentially lead to future therapeutic improvements for infected elderly patients. The proposed project also has for a goal to recruit and train a diverse body of students who will represent the next generation of scholars in the science, technology, engineering, and mathematics (STEM).