Parasitoid wasps are abundant free-living insects that inject venom into and then lay their eggs on other insects. Parasitoids vary in hosts they utilize (flies, beetles, butterflies, etc), the life stage they parasitize (eggs, larvae, pupae), and whether their eggs are laid and develop within or outside the host. Due to this diversity, parasitoid venoms have evolved different mechanisms for manipulating host immunity, physiology and behavior in ways that enhance development of the parasitoid young. Among their effects, venoms can induce temporary or permanent paralysis, selective apoptosis, and alterations in host lipid physiology, immunity, and behavior. Yet virtually nothing is known about the diversity or function of individual parasitoid venom proteins. There are over 150,000 species of parasitoids. The model parasitoid Nasonia vitripennis alone has at least 79 different venom genes, of which 24 have no sequence similarity to any known proteins and contain no known conserved domains. Given their incredible number and diversity, parasitoids venoms represent an immense and untapped potential resource for drug discovery. The challenge is to efficiently assess this immense potential pharmacopeia for molecules with medical and research applications. Small biologically active peptides are particularly promising as therapeutic agents, and therefore their detection in parasitoid venoms is an important goal. We predict that evolutionary conservation in novel venom proteins can be used to identify short peptides with biological activity of relevance to medicine and research. If correct, this approach could rapidly accelerate new drug discovery among the immense pool of parasitoid venom proteins. Here we propose to investigate (a) the effects of individual Nasonia venom proteins in the whole animal Sarcophaga bullata (flesh fly) and in human cell lines by transcriptome, proteome, and physiological profiling, (b) assess the diversity of evolution of parasitoid venoms and identify conserved short peptides, and (c) test the hypothesis that evolutionary conservation can be used to predict short bioactive peptides, using our whole animal and human cell line assays. The project combines genetic, proteomic, physiological and evolutionary approaches to explore function, diversity, and potential for drug discovery in the immense pool of parasitoid venom proteins.

Public Health Relevance

Parasitoid venoms represent a huge but untapped potential reservoir for the discovery of new bioactive compounds and drugs. However, their function and diversity is relatively unexplored. Here we assess functions of different proteins in the rich venom repertoire of Nasonia, and whether short peptides with medically relevant effects can be efficiently identified. This project lays the groundwork for future exploitation of the vast reservoir of parasitoid venoms in medicine and basic research.

National Institute of Health (NIH)
National Institute of General Medical Sciences (NIGMS)
Research Project (R01)
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Special Emphasis Panel (ZGM1-GDB-7 (EU))
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Fabian, Miles
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University of Rochester
Schools of Arts and Sciences
United States
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Martinson, Ellen O; Werren, John H (2018) Venom is beneficial but not essential for development and survival of Nasonia. Ecol Entomol 43:146-153
Wang, Fei; Fang, Qi; Wang, Beibei et al. (2017) A novel negative-stranded RNA virus mediates sex ratio in its parasitoid host. PLoS Pathog 13:e1006201
Martinson, Ellen O; Mrinalini; Kelkar, Yogeshwar D et al. (2017) The Evolution of Venom by Co-option of Single-Copy Genes. Curr Biol 27:2007-2013.e8
Yan, Zhichao; Fang, Qi; Liu, Yang et al. (2017) A Venom Serpin Splicing Isoform of the Endoparasitoid Wasp Pteromalus puparum Suppresses Host Prophenoloxidase Cascade by Forming Complexes with Host Hemolymph Proteinases. J Biol Chem 292:1038-1051
Wang, Xu; Werren, John H; Clark, Andrew G (2016) Allele-Specific Transcriptome and Methylome Analysis Reveals Stable Inheritance and Cis-Regulation of DNA Methylation in Nasonia. PLoS Biol 14:e1002500
Martinson, Ellen O; Martinson, Vincent G; Edwards, Rachel et al. (2016) Laterally Transferred Gene Recruited as a Venom in Parasitoid Wasps. Mol Biol Evol 33:1042-52
Yan, Zhichao; Fang, Qi; Wang, Lei et al. (2016) Insights into the venom composition and evolution of an endoparasitoid wasp by combining proteomic and transcriptomic analyses. Sci Rep 6:19604
Werren, John H; Cohen, Lorna B; Gadau, Juergen et al. (2016) Dissection of the complex genetic basis of craniofacial anomalies using haploid genetics and interspecies hybrids in Nasonia wasps. Dev Biol 415:391-405
Siebert, Aisha L; Wheeler, David; Werren, John H (2015) A new approach for investigating venom function applied to venom calreticulin in a parasitoid wasp. Toxicon 107:304-16
Mrinalini; Siebert, Aisha L; Wright, Jeremy et al. (2015) PARASITOID VENOM INDUCES METABOLIC CASCADES IN FLY HOSTS. Metabolomics 11:350-366

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