68 Oral - Immunity and Microbiome
Friday April 08, 9:00 AM - 9:15 AM

Authors:
William H. Pearson ¹; Krista L. Grimes ¹; Ashima D. Wadhawan ¹; Jake Jacobson ¹; Esteban J. Beckwith ²; Gerald Larrouy-Maumus ¹; Marc S. Dionne ¹

Affiliations:
1) Centre for Molecular Bacteriology and Infection, Imperial College London, UK; 2) Instituto de Fisiología, Biología Molecular y Neurociencias, UBA-CONICET, Buenos Aires, Argentina

Keywords:
o. other (Immunometabolism); t. other (Immunometabolism)

Immunity and metabolism are closely intertwined. Immune responses are resource-demanding and metabolic changes are therefore required to the supply the immune system with the required energy and raw materials. In pathological infections where the immune response becomes dysregulated, these metabolic changes can contribute to pathology. Work using the model organism Drosophila melanogaster has been productive in uncovering how the immune system regulates metabolism, but details of actual metabolic changes that occur during infection, and their functions, are poorly known.
This project seeks to uncover the metabolic changes that occur during the Drosophila innate immune response to infection and understand the consequences of these changes. By combining mass spectrometry-based metabolomic analysis with genetic approaches, we found that successful immune responses to systemic bacterial infection caused an increase in nitrogenous waste metabolism. Further investigations suggested that this increase in nitrogenous waste is due to upregulation of endogenous protein degradation via an ESCRT-III mediated process. Expression of CHMP2B, encoding a core ESCRT-III component, is indicated to be required in fat body for the optimal translation of antimicrobial peptide transcripts. Together these data suggest a model in which the fly upregulates degradation of its own protein in order to rapidly provide in-demand amino acids for immune effector production, with catabolism of the resulting excess amino acids causing an increase in nitrogen waste metabolism. This project has thus revealed a profound metabolic change induced by a successful immune response in Drosophila. As the cost of this change is the degradation of the host’s own protein, this a probable mechanism of metabolic pathology in the context of a dysregulated immune response. Studying the etiology of such metabolic pathology will contribute to our understanding of conditions underpinned by metabolic dysregulation, such as sepsis and infection-induced cachexia.