The Drosophila Pvr Pathway Regulates Innate Immunity and Intestinal Homeostasis

  • Author / Creator
    Bond, David JE
  • 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.

  • Subjects / Keywords
  • Graduation date
  • Type of Item
  • Degree
    Doctor of Philosophy
  • DOI
  • License
    This thesis is made available by the University of Alberta Libraries with permission of the copyright owner solely for non-commercial purposes. This thesis, or any portion thereof, may not otherwise be copied or reproduced without the written consent of the copyright owner, except to the extent permitted by Canadian copyright law.
  • Language
  • Institution
    University of Alberta
  • Degree level
  • Department
    • Department of Medical Microbiology and Immunology
  • Specialization
    • Immunology
  • Supervisor / co-supervisor and their department(s)
    • Foley, Edan (Medical Microbiology and Immunology)
  • Examining committee members and their departments
    • Hughes, Sarah (Medical Genetics)
    • Burshtyn, Deborah (Medical Microbiology and Immunology)
    • Rast, Jonathan (Medical Biophysics)
    • Smiley, James (Medical Microbiology and Immunology)