Abstract
Immune and metabolic pathways collectively influence host responses to microbial invaders, and mutations in one pathway frequently disrupt activity in another. We used the Drosophila melanogaster model to characterize metabolic homeostasis in flies with modified immune deficiency (IMD) pathway activity. The IMD pathway is very similar to the mammalian TNF-α pathway, a key regulator of vertebrate immunity and metabolism. We found that persistent activation of IMD resulted in hyperglycemia, depleted fat reserves, and developmental delays, implicating IMD in metabolic regulation. Consistent with this hypothesis, we found that imd mutants weigh more, are hyperlipidemic, and have impaired glucose tolerance. To test the importance of metabolic regulation for host responses to bacterial infection, we challenged insulin pathway mutants with lethal doses of several Drosophila pathogens. We 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. Combined, our results support a role for coordinated regulation of immune and metabolic pathways in host containment of microbial invaders.
Highlights
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Serial dilutions of fly homogenates were made in 96-well plates, and 10 ml of spots were plated on lysogeny broth (LB) agar supplemented with 100 mg/ml streptomycin, brain heart infusion (BHI) agar, and LB agar for the rest of the bacteria
Activation of immune deficiency (IMD) deregulated the expression of 1188 genes in third instar larvae by a factor of 1.5 or more (Supplemental Table I)
Summary
Adult flies and larvae were raised on standard corn meal medium (NutriFly Bloomington formulation, https://bdsc.indiana.edu/information/recipes/ bloomfood.html; Genesse Scientific). For total triglyceride (TG) measurement, 10 third instar larvae or 5 adult flies were weighed and homogenized in TE buffer with 0.1% Triton X-100. We added 500 ml of PBS with 1% Triton X-100 to the tubes with the remaining flies and mashed the samples using a pestle and cordless motor (VWR 47747-370), followed by a 5-min vortex at maximum speed. We centrifuged these tubes at maximum speed for 5 min and transferred 50 ml of the supernatant to a PCR tube as our total ILP2HF sample. The top 15 Gene Ontology (GO) terms sorted by p value were selected for both upregulated and downregulated analyses, ranked by enrichment score, and visualized using the easyggplot package in R (version 1.1.442)
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