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Mitochondrial-derived glutamate dictates resistance to pathogen infection through vitamin-dependent metabolic remodeling

ABSTRACT: The functional integration of innate immune and metabolic signaling responses represents an ancient strategy to manage infections in metazoans. Using Drosophila, we uncovered that immune-metabolic sensing in muscle dictates resistance to enteric bacterial infection through vitamins dependent metabolic remodeling. Within muscle, the activation strength of systemic innate immune signaling, integrated with mitochondrial-dependent glutamate dehydrogenase (Gdh) function, conditions lipid mobilization from adipose. Mild intramuscular IMD/innate immune signaling activity allows for infection-mediated increases in mitochondrial biogenesis/function, which further stimulates mitochondria/Gdh-dependent synthesis of glutamate. Intramuscular derived glutamate acts as a systemic metabolite to influence lipid mobilization through altering vitamin metabolism. This lipid mobilization improves bacterial clearance and boost infection resistance. Conversely, elevated activation of IMD/innate immune signaling in muscle impedes infection-mediated increases in mitochondrial biogenesis/function and subsequent metabolic remodeling. Finally, life history traits that fine-tune intramuscular mitochondrial dynamics consequently influence infection resistance and shape phenotypic diversity of infection responses within populations.

ORGANISM(S): Drosophila melanogaster

PROVIDER: GSE160652 | GEO | 2021/11/19

REPOSITORIES: GEO

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Project description:Mosquitoes possess an innate immune system that is capable of limiting infection by a variety of pathogens, including the Plasmodium spp. parasites responsible for human malaria. The Anopheles immune deficiency (IMD) innate immune signaling pathway confers resistance to Plasmodium falciparum. While some previously identified Anopheles anti-Plasmodium effectors are regulated through signaling by Rel2, the transcription factor of the IMD pathway, many components of this defense system remain uncharacterized. To begin to better understand the regulation of immune effector proteins by the IMD pathway, we used oligonucleotide microarrays and iTRAQ to analyze differences in mRNA and protein expression, respectively, between transgenic An. stephensi mosquitoes exhibiting blood meal-inducible overexpression of an active recombinant Rel2 and their wild-type conspecifics. Numerous genes were differentially regulated at both the mRNA and protein levels following induction of Rel2. While multiple immune genes were up-regulated, a majority of the differentially expressed genes have no known immune function in mosquitoes. Identified sequences were assigned putative functions and gene ontology (GO) terms based on homology to previously annotated A. gambiae gene sequences. Selected up-regulated genes from multiple GO categories were tested for both anti-Plasmodium and anti-bacterial action using RNA interference (RNAi). Based on our experimental findings, we conclude that increased expression of the IMD immune pathway-controlled transcription factor Rel2 affects the expression of numerous genes with diverse functions, suggesting a broader physiological impact of immune activation and possible functional versatility of Rel2. Our study has identified multiple novel anti-Plasmodium effectors. Midguts from midgut-specific transgenic A. stephensi at 6 and 12 hours post-blood meal and fat bodies from fat body-specific transgenic A. stephensi at 12 and 18 hours post-blood meal were compared to wild-type A. stephensi at the same time points. 3 biological replicates and 1 pseudo-replicate per array.

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Mitochondrial-derived glutamate dictates resistance to pathogen infection through vitamin-dependent metabolic remodeling

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