JAK/STAT signaling in Drosophila acute phase response

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DESCRIPTION (provided by applicant): In mammals, local disturbances of physiological homeostasis such as septic injury lead to a systemic response known as the acute phase response. A major early step in this process is the release of signaling molecules such as cytokines by activated immune cells, including blood cells. Upon systemic release, these cytokines activate signaling pathways in various organs, including the JAK/STAT signaling pathway in the liver. This leads to activation of target genes coding for serum proteins such as CRP, thus leading to dramatic changes in blood concentrations of these acute phase proteins. We have recently discovered that septic injury triggers a similar acute phase response in Drosophila. We have shown that the expression of the cytokine-like molecule Upd3 is activated in blood cells upon immune challenge. Our genetic analysis demonstrates that, in response to septic injury, activated blood cells produce a cytokine, Upd3, which is necessary to activate the JAK/STAT pathway in the fat body, an organ functionally equivalent to the mammalian liver. Activation of JAK/STAT signaling controls the expression of target genes, such as totA, a gene encoding a small peptide released into the hemolymph (insect blood). Flies deficient in JAK/STAT signaling in fat body display defects in immune functions including phagocytosis and resistance to infection with pathogenic bacteria, such as Listeria. Our hypothesis is that, upon septic injury, hemocytes sense the infection process and release signaling molecules that lead to activation of JAK/STAT signaling in the fat body and subsequent release of JAK/STAT-regulated effectors that, in return, assist hemocytes in accomplishing their immune functions. To test our hypothesis, we have designed a number of genetic experiments to further characterize the JAK/STAT-regulated acute phase response in Drosophila. In particular, we propose (1) to identify the signals and the signaling pathways leading to upd3 hemocyte activation in response to septic injury, (2) to characterize the various components involved in JAK/STAT signaling and (3) to identify and characterize the JAK/STAT-regulated effectors that modulate hemocyte functions. By taking advantage of powerful genetic strategies available in Drosophila, these studies will advance our understanding of complex integrated physiological responses involving various cell types, such as hemocytes and fat body cells and will likely uncover novel mechanisms related to innate immunity. Our work in Drosophila may help understand the role of the acute phase response in mammals, a remarkable homoeostatic response that has been apparently conserved throughout evolution.