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The Drosophila Pvr Pathway Regulates Innate Immunity and Intestinal Homeostasis Open Access

Descriptions

Other title
Subject/Keyword
IMD pathway
RNAi
Drosophila
intesitinal stem cells
JNK
Pvr
innate immunity
Type of item
Thesis
Degree grantor
University of Alberta
Author or creator
Bond, David JE
Supervisor and department
Foley, Edan (Medical Microbiology and Immunology)
Examining committee member and department
Burshtyn, Deborah (Medical Microbiology and Immunology)
Rast, Jonathan (Medical Biophysics)
Hughes, Sarah (Medical Genetics)
Smiley, James (Medical Microbiology and Immunology)
Department
Department of Medical Microbiology and Immunology
Specialization
Immunology
Date accepted
2013-01-30T15:23:07Z
Graduation date
2013-06
Degree
Doctor of Philosophy
Degree level
Doctoral
Abstract
The innate immune system is an evolutionarily conserved first line of defense against invasive microbes. Studies in the fruit fly, Drosophila melanogaster, revolutionized the field of immunology and cemented Drosophila as a premier model of innate immune defenses. The Drosophila immune deficiency (IMD) pathway detects bacterial DAP-type peptidoglycan and drives protective immune responses. The IMD pathway shares remarkable conservation of downstream signaling components with the human Tumor Necrosis Factor (TNF) pathway, including engagement of caspase, NF-κB and Jun-N-terminal kinase (JNK) modules. Given conserved and pleiotropic roles of JNK in eukaryote biology, I performed the first quantitative high-throughput RNAi screen to identify novel regulators of Drosophila JNK (dJNK) activity in the IMD pathway. I identified numerous novel negative and positive regulators of dJNK signaling including the receptor tyrosine kinase PDGF- and VEGF- receptor related (PVR) pathway. Follow-up studies uncovered a previously unknown negative-feed back loop, whereby IMD pathway activation of dJNK results in the production of Pvr-ligands, pvf2 and pvf3, and engagement of the PVR pathway, which in turn suppresses IMD immune responses. I extended these findings to the Drosophila posterior midgut (mammalian small intestine equivalent), a well-established in vivo model to study the genetic interplay between protective innate immune responses and potentially damaging environmental insults. The Drosophila intestine serves as a critical immunological barrier at the interface between a delicate internal milieu and a hostile microbial environment. The posterior midgut contains a dynamic pool of intestinal stem cells (ISC) that rapidly proliferate and differentiate into mature epithelial cells to maintain epithelial integrity in response to environmental toxins. My findings establish that Pvf/Pvr autocrine signals are essential for ISC homeostatic proliferation and differentiation, and that loss of Pvr signals leads to midgut hypoplasia. I determined that extrinsic stress signals generated by enteropathoganic infection are epistatic to the hypoplasia generated in pvr mutants, making the PVR pathway unique among all previously studied intrinsic pathways. Together, these studies revealed the PVR pathway as a critical regulator of Drosophila innate immune defenses and intestinal homeostasis.
Language
English
DOI
doi:10.7939/R33W8S
Rights
Permission is hereby granted to the University of Alberta Libraries to reproduce single copies of this thesis and to lend or sell such copies for private, scholarly or scientific research purposes only. Where the thesis is converted to, or otherwise made available in digital form, the University of Alberta will advise potential users of the thesis of these terms. The author reserves all other publication and other rights in association with the copyright in the thesis and, except as herein before provided, neither the thesis nor any substantial portion thereof may be printed or otherwise reproduced in any material form whatsoever without the author's prior written permission.
Citation for previous publication
Bond, D., Primrose, D.A., and Foley, E. (2008). Quantitative evaluation of signaling events in Drosophila S2 cells. Biological Procedures Online 10, 20-28.Bond, D., and Foley, E. (2009). A quantitative RNAi screen for JNK modifiers identifies Pvr as a novel regulator of Drosophila immune signaling. PLoS Pathogens 5, e1000655.Bond, D., and Foley, E. (2012). Autocrine PDGF- VEGF- receptor related (Pvr) pathway activity controls intestinal stem cell proliferation in the adult Drosophila midgut. The Journal of Biological Chemistry.

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