JAK/STAT pathway in autophagic control of intracellular mycobacteria. Claire Péan, Sharon W.S.Tan, Marc Dionne. CMCBI, Kings College London, London, United Kingdom.

   The Jak/Stat pathway has been extensively studied during the past 20 years and the function of each Jak, Stat and Socs protein has been analyzed in all cell types involved in the inflammatory response in mammals. However, despite a broad literature on Jak/Stat in innate immunity, we still do not understand the in vivo consequences of these signals, especially in the control of infection with pathogens.
   In human cells, part of the difficulty in understanding how the pathway regulates inflammation is the presence of complex compensatory mechanisms between the different Jak and stat proteins. In flies, there is only one Jak, one stat and a few cytokines. In the Dionne lab, we use Drosophila melanogaster as a model to study in vivo activation of the Jak/stat pathway upon mycobacterial infection.
   We show that, in Drosophila, blockade of Jak/Stat signalling is beneficial for the host upon mycobacterial infection. Loss of upd3 and inhibition of Stat92E or dome in hemocytes all improve survival and decrease bacterial growth and hemocyte death. Strikingly, we find that Jak/Stat signaling inhibits autophagy gene expression in hemocytes in vivo, partly by activating expression of a transcriptional repressor. We also show that promoting autophagy in phagocytes can reduce bacterial numbers, indicating that in flies, as in mammals, autophagy plays a role in killing intracellular mycobacteria.
   We thus show a mechanism by which Jak/stat inhibits autophagy gene expression and demonstrate that this inhibition is detrimental to the survival of the host.