Regulation of Host Signaling by Parasitoid Venom Proteins

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The precise regulation of intra- and inter-cellular signaling events is crucial for the function of biological systems and plays an essential role in human health. Deregulated signaling can perturb cell function by altering the timing or strength of signal activity and can contribute to the pathogenesis of multiple diseases. Signal regulation is accomplished by a variety of intrinsic mechanisms, but signaling can also be manipulated by extrinsic factors including factors derived from other organisms or the environment. Interorganismal signal regulation is often observed during infection, in which a parasite can utilize virulence factors in order to alter host signaling events. In my lab we use the Drosophila-parasitoid wasp host-parasite system as a model to study the mechanisms used by parasites to manipulate host signaling. These parasitoids contain virulence proteins in their venoms, and work from my lab has demonstrated that parasitoid venom proteins can modify conserved signaling mechanisms including signal transduction pathways and second messenger systems in their hosts. Understanding the mechanistic basis of these venom protein activities will provide a powerful tool to study the regulation of signaling events, and will allow us to gain novel insight into conserved signaling mechanisms in Drosophila, an important model of human health. The objective of our research is to leverage this system to uncover novel mechanisms underlying signal regulation and to achieve these goals, research in my lab will focus on: 1) Identifying the molecular mechanisms used by parasitoid wasps to inhibit conserved signaling pathways in their Drosophila hosts. We have found that distinct parasitoid species target specific signaling pathways in their hosts, including species that specifically inhibit the JAK-STAT, NFκB and JNK signal transduction pathways. These pathways play vital roles in human health and this research will provide important insight into their regulation. 2) Characterizing the ability of predicted dominant negative proteins to regulate host signaling. Our bioinformatic analyses have identified several putative dominant negative proteins within parasitoid venom. We predict that these proteins will deregulate diverse signaling activities including immune receptor signaling and cytoskeletal rearrangements. From these experiments we will gain a better understanding of the roles played by the targeted proteins in a range of signaling events. 3) Investigating the basis for the tissue specificity of parasitoid venom activity. We have found that the ability of parasitoids to regulate signaling is highly tissue specific within the host. These experiments will explore the basis of this observation and provide insight into the mechanisms that underlie tissue specific signal regulation. The knowledge gained from this research will help to elucidate general principles underlying the regulation of signaling, and will provide specific information about multiple pathways and signaling mechanisms linked to human health. In addition, these findings could be applied to the development of new therapeutics that could be utilized for a variety of human diseases that share common molecular mechanisms.