Glucose and trehalose metabolism through the cyclic pentose phosphate pathway shape pathogen resistance and host protection in Drosophila

Activation of immune cells requires the remodeling of cell metabolism in order to support immune function. We study these metabolic changes through the infection of Drosophila larvae by parasitoid wasp. Neutralization of the parasitoid egg involves the differentiation of lamellocytes, which encapsulate the egg. A melanization cascade is initiated, producing toxic molecules to destroy the egg; meanwhile the capsule created also protects the host from the toxic reaction. We combine transcriptomics and metabolomics, including 13C-labeled glucose and trehalose tracing, as well as genetic manipulation of sugar metabolism to study changes in metabolism, specifically in Drosophila hemocytes. We found that hemocytes increase the expression of several carbohydrate transporters, and accordingly uptake of sugar during infection. These carbohydrates are metabolized by increased glycolysis, associated with lactate production, and cyclic pentose phosphate pathway (PPP), in which glucose-6-phosphate is re-oxidized to maximize NADPH production. Oxidative PPP is required for lamellocyte differentiation and resistance, as is systemic trehalose metabolism. In addition, fully differentiated lamellocytes use a cytoplasmic form of trehalase to cleave trehalose to glucose, within the cell, to fuel cyclic PPP. Intracellular trehalose metabolism is not required for lamellocytes differentiation, but its downregulation increases reactive oxygen species levels, associated with increased resistance and decreased fitness. Thus, our results suggest that sugar metabolism within immune cells, and specifically in cyclic PPP, may be important for not only fighting infection, but also for protecting the host from its own immune response and ensuring sufficient fitness of the survivor.