Akt and foxo dysregulation contribute to infection-induced wasting in Drosophila

Background: Studies in Drosophila have taught us a great deal about how animals regulate the immediate innate immune response, but we still know little about how infections cause pathology. Here, we examine the pathogenesis associated with Mycobacterium marinum infection in the fly. M. marinum is closely related to M. tuberculosis, which causes tuberculosis in people. Results: A microarray analysis showed that metabolism is profoundly affected in M. marinum-infected flies. A genetic screen identified foxo mutants as slower-dying after infection than wild-type flies. FOXO activity is inhibited by the insulin effector kinase Akt; we show that Akt activation is systemically reduced as a result of M. marinum infection. Finally, we show that flies infected with Mycobacterium marinum undergo a process like wasting: They progressively lose metabolic stores, in the form of fat and glycogen. They also become hyperglycemic. In contrast, foxo mutants exhibit less wasting. Conclusions: In people, many infections-including tuberculosis-can cause wasting, much as we see in Drosophila. Our study is the first examination of the metabolic consequences of infection in a genetically tractable invertebrate and gives insight into the metabolic consequences of mycobacterial infection, implicating impaired insulin signaling as a key mediator of these events. These results suggest that the fly can be used to study more than the immediate innate immune response to infection; it can also be used to understand the physiological consequences of infection and the immune response.