Dissertation
Insulin and the Non-replicative DNA virus IIV-6 Prime a JAK/STAT-mediated Immune Response that Restricts Insect-borne Viruses in Invertebrate and Vertebrate Hosts
Doctor of Philosophy (PhD), Washington State University
01/2019
Handle:
https://hdl.handle.net/2376/110668
Abstract
Innate immunity refers to the body's initial defensive response upon exposure to invading organisms. During pathogenic infection, the innate immune response is initiated by the activation of receptors upon recognition of conserved molecular patterns, such as nucleic acids from a virus' genome or replicative cycle. The detection of pathogen-associated molecules is an ancient form of host defense, and innate immune pathways are conserved even between diverse phyla. This is significant because some pathogens are able to infect multiple species -- for example, arboviruses, which can infect both an arthropod vector and a mammalian host. The World Health Organization estimates that over half of the world’s population is at risk for vector-borne diseases, including arboviruses. These viruses infect both mammals and insects, so the identification of conserved and disparate immune signaling pathways could influence vector control methods. For these reasons, this work utilizes Drosophila melanogaster, a well-established model organism, for two types of comparative analyses: to identify conserved features of insect and mammalian immunity to the insect virus Invertebrate iridescent virus 6 (IIV-6), and to establish similarities in immune signaling between flies and mosquitoes during West Nile virus (WNV) infection. In the first comparison, this work demonstrates that IIV-6 induces an antiviral immune response in mammalian cells mediated by the viral RNA sensors RIG-I and MDA5, which share a conserved helicase domain with the D. melanogaster immune protein Dicer-2. Notably, the mammalian innate immune response to IIV-6 is functionally capable of protecting cells from subsequent infection with the arboviruses Vesicular stomatitis virus and WNV (Kunjin strain). In the second comparison this work identifies the insulin-like receptor as a novel component of the D. melanogaster immune response to WNV (Kunjin strain) and translates this finding to mosquitoes in vitro and in vivo. This work demonstrates that priming mosquito cells and Culex mosquitoes with vertebrate insulin leads to reduced viral titer of WNV, dengue virus, and Zika virus. Altogether, this work compares the immune responses of diverse phyla during virus infection to identify conserved features that can inform vector control and identify novel avenues for therapeutic design.
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Details
- Title
- Insulin and the Non-replicative DNA virus IIV-6 Prime a JAK/STAT-mediated Immune Response that Restricts Insect-borne Viruses in Invertebrate and Vertebrate Hosts
- Creators
- Laura Ahlers
- Contributors
- Alan G Goodman (Advisor)Michael E Konkel (Committee Member)Anthony V Nicola (Committee Member)Philip F Mixter (Committee Member)
- Awarding Institution
- Washington State University
- Academic Unit
- School of Molecular Biosciences
- Theses and Dissertations
- Doctor of Philosophy (PhD), Washington State University
- Number of pages
- 169
- Identifiers
- 99900581616001842
- Language
- English
- Resource Type
- Dissertation