Mechanisms of interaction between sleep and the innate immune response in Drosophila

University Of Pennsylvania, Philadelphia PA

Investigators

Abstract

During an immune challenge, a host will adapt its behavior in a manner that enhances its ability to overcome that challenge. In mammals, this adaptive behavior is often manifested as increased sleep. The complex relationship between sleep and the immune response is not well understood at either the functional or the molecular level. In an effort to understand this relationship, this project exploits the Drosophila genetic model. The fruit fly Drosophila is a powerful model system that exhibits all of the behavioral features associated with sleep. The innate immune response in this species is also well characterized and has many features that are shared with that in mammals. Central to this reciprocal relationship between sleep and immune function is a family of transcription factor genes, NFκB. The first aim will test the hypothesis that, in the absence of infection, NFκB activity progressively increases during wakefulness and promotes sleep after reaching a threshold. Sleep then leads to decreased NFκB levels. Real time daily activity levels of NFκB in living flies will be measured using a reporter assay that was developed in the PI's laboratory. Flies that lack one or more NFκB genes are also expected to have severely reduced sleep. Second, following bacterial infection there is a large burst in NFκB that peaks 6-12 hours after the infection and promotes sleep. Manipulations of sleep using mechanical or genetic methods will be used to disrupt this burst of NFκB activity and to affect immune function. Specifically, manipulations that enhance peak NFκB activity after the infection as well as the ensuing recovery sleep will improve immune function as measured by rates of survival. Conversely, sustaining high levels of NFκB by blocking a recovery sleep will decrease immune function. Results of this work will provide important mechanistic insight into how sleep as an adaptive behavior influences immune function. Understanding molecular mechanisms of adaptive behavior during an immune response in insects has important agricultural implications as well as for mammalian biology. This project will provide educational opportunities for a post-doctoral trainee, undergraduate, and high school students. The PI is committed to participating in educational programs that benefit individuals from groups which are traditionally underrepresented in the sciences.