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National Yang-Ming University
Graduate Program of Cellular & Molecular Pharmacolog
Thesis Advisor: Julie A. Williams, PhD
Friday, March 12, 2010
Increased sleep and fatigue are commonly experienced during illness. In mammalian systems, this effect is known to be mediated by immune response modulators such as cytokines and Nuclear factor kappaB (NFkappaB). However, the function of this increased sleep during a recovery process, as well as the underlying mechanism are not clear. To address this challenging problem, the simple genetic model system, the fruit fly Drosophila melanogaster, was used to study the reciprocal interaction between sleep and the immune response. We first established that similar to mammals, the immune response promotes sleep in flies. The increase in sleep is gated by the circadian clock and requires NFkappaB Relish, a key component of innate immunity in Drosophila. We next tested the hypothesis that sleep during infection promotes recovery. Infection normally increases NFkappaB and transiently increases sleep. We propose that a function of sleep is to down regulate NFkappaB during infection. Sleep deprivation prior to infection is therefore predicted to enhance recovery sleep and NFkappaB activity and thereby increase survival during an infection. Results of our studies support this hypothesis. Furthermore, two Drosophila NFkappaBs, Dif and Relish are required for the protective effect mediated by sleep deprivation prior to infection. We next used a genetic approach to manipulate sleep. Specifically, we genetically altered neuronal excitability in the mushroom body, a region in the central brain that regulates learning and sleep. Increasing sleep using this method strongly promoted survival during infection. Decreasing sleep, on the other hand, did not produce a net change in survival outcome. However, the increased bacterial clearance in these flies suggested that long-term sleep loss reduces tolerance to infection. In conclusion, these findings indicate a complex interaction between sleep and the immune response in Drosophila and suggest that sleep during an immune response is beneficial for the recovery process.