Characterization of the crosstalk between immunity and metabolism in Drosophila melanogaster model

• Author / Creator

  Davoodi, Saeideh

• Immune and metabolic pathways collectively contribute to the containment of microbial invaders, and persistent activation of immune responses contribute to the development of severe metabolic disorders. To determine how interaction between innate immune system and metabolic responses affected host health as well as host response to microbial invaders, I used the Drosophila model. The fat body in Drosophila coordinates immune, growth and metabolic pathways which are evolutionary conserved between flies and mammals. The immune deficiency (IMD) pathway in Drosophila is very similar to the mammalian TNF-α pathway, a key regulator of vertebrate immunity and metabolism. To determine how a prolonged immune response impacts metabolism, I induced a constitutive inflammatory response in the Drosophila fat body, a key regulator of humoral immunity and metabolic homeostasis. Through whole-genome microarray analysis, I found that persistent immune activity in the larval fat body resulted in suppression of expression of genes involved in glycolysis, lipid synthesis and insulin signaling. In contrast, I found genes involved in glycogenolysis and apoptosis were highly expressed in larvae with consistent IMD activity in the fat body. I looked at macronutrients levels in whole larvae as well as in the hemolymph and found reduction in triglyceride contents as well as hyperglycemia in circulatory hemolymph. I also showed that elevated IMD activity in the larval fat body replicated key features of a suppressed insulin pathway such as delayed development, reduced body size, and hyperglycemia. Consistent with the role of IMD in metabolic homeostasis, I found that imd mutants weigh more, are hyperlipidemic, and have impaired glucose tolerance. Combined these results showed that persistent activation of IMD in the larval fat body has detrimental effects on metabolism, development and growth of the larvae and IMD is required for metabolic homeostasis. To test the importance of metabolic regulation for host responses to bacterial infection, I challenged
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  insulin pathway mutants with lethal doses of several Drosophila pathogens and I measured survival and bacterial load.
  I found that loss-of-function mutations in the insulin pathway impacted host responses to infection in a manner that depends on the route of infection and the identity of the infectious microbe. Specifically, I found that enteric pathogen, Vibrio cholerae, disrupts glucose metabolism in adult flies and results in elevation of circulatory glucose. I showed oral infection of adult females with a holidic diet supplemented with glucose extends survival of flies upon enteric V. cholerae infection. Combined, my results support a role for coordinated regulation of immune and metabolic pathways in host containment of microbial invaders. Mechanistically, it is unclear how an immune–metabolic axis influences host responses to bacterial infection. Immunity encompasses resistance mechanisms that kill infectious microbes and tolerance mechanisms that mitigate disease severity without effects on microbial load. I studied how modulation of IMD or insulin signalling in the fat body affects host defence response towards oral infection with V. cholerae. I found that inhibition of insulin pathway in the fat body results in increased survival of flies upon oral infection with the V. cholerae while the bacterial number remained unchanged and V. cholerae persisted longer in the host in the absence of pathogen feeding as well. Additionally, suppression of IMD pathway in the fat body resulted in survival extension after oral infection with V. cholerae while the bacterial load was significantly higher in these flies. These observations suggest an improved tolerance towards V. cholerae is induced in the fly once IMD or insulin pathway are not functional in the fat body. Combined, my data reveal persistent immune activity in the fat body disrupts host growth and metabolism, uncovers the role of host insulin signaling in host-pathogen interaction, and indicate the protective role of immune and metabolic suppression in a metabolic tissue against an intestinal pathogen, V. cholerae

• Subjects / Keywords

  • insulin
  • immunity
  • Vibrio cholerae
  • fat body
  • Drosophila
  • IMD pathway

• Graduation date

  Fall 2021

• Type of Item

  Thesis

• Degree

  Doctor of Philosophy

• DOI

  https://doi.org/10.7939/r3-0bhx-5r30

• 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.