Immunity and metabolism are closely interlinked processes. Mounting an immune response is costly, and therefore metabolism is altered upon infection to provide the necessary energy and raw materials. In serious or prolonged infection, these immune-induced metabolic changes can be a driver of pathology. Drosophila melanogaster has been a widely used model for the study of interplay between immunity and metabolism. However, many of the signalling mechanisms linking immune detection with metabolic regulation, and their specific consequences for infection course and outcome, remain to be explored.
In this work, I used Targeted DamID to generate a transcriptional profile of the fat body during infection. The fat body is the predominant site of energy storage and intermediary metabolism but also coordinates humoral immunity, and is thus a critical tissue for immune-metabolic interaction in Drosophila. I determined that the fly responds to many bacteria by altering expression of genes of the folate cycle and associated enzymes of amino acid metabolism. These transcriptional changes occur in a manner that would increase flow of carbon from glycolysis into serine and glycine synthesis and increase folate cycle flux through the mitochondrion. I determined that the two most highly induced enzymes, astray and Nmdmc, are repressed in healthy flies by the transcription factor MEF2. This repression is overcome upon infection by the coordinated action of major immune and metabolic transcription factors Dif and FOXO. The transcriptional regulation of these serine-folate metabolic unit enzymes has functional consequence for immunity, as knockdowns and mutants present altered resistance and tolerance phenotypes, in a pathogen-specific manner. This work has thus uncovered the immune-induced signalling that regulates a novel metabolic unit of functional importance during infection.