Though mammalian JAKs and STATs have been extensively studied over the past 20 years, many aspects of their in vivo function remain unclear. In particular, their roles in control of infection with pathogens remain murky and confusing. One difficulty in understanding how these pathways regulate inflammation is the presence of complex compensatory mechanisms between the different JAK and STAT proteins. In the Dionne lab, we use the fruit-fly Drosophila melanogaster as a model to study the in vivo functions of the JAK/STAT pathway in mycobacterial infection. Flies contain only one JAK (hop), one STAT (STAT92E), and three identified interleukin-like signals to activate signalling (upd, upd2, upd3). I show that, in Drosophila, the STAT-activating cytokine Upd3 is harmful to the host upon mycobacterial infection. Flies lacking upd3, or in which the JAk/STAT pathway is inhibited in phagocytes, show improved survival, decreased mycobacterial numbers, and delayed immune cell death. Strikingly, I find that JAK/STAT signalling acts in concert with other inflammatory signals to regulate expression of Atg2 in Drosophila phagocytes. In isolation or upon infection, STAT activation inhibits Atg2 expression and the ability of other, unknown signals to promote Atg2 expression. Increased Atg2 expression, as is seen in infected animals lacking either the cytokine Upd3 or STAT92E, promotes killing of intracellular bacteria and accumulation of large lipid droplets of unusual shape. I suggest an autophagy-independent mechanism by which Atg2 could reduce bacterial growth, involving the control of lipid body morphology. In this thesis, I show a mechanism by which JAK/STAT controls bacterial growth through inhibition of autophagy gene expression and demonstrate that this inhibition is detrimental to the survival of the host. In addition, I demonstrate that upd3 signalling is also required for glucose homeostasis suggesting a role for Upd3 in regulating gluconeogenesis and glycolysis.
| Identifer | oai:union.ndltd.org:bl.uk/oai:ethos.bl.uk:628431 |
| Date | January 2013 |
| Creators | Pean, Claire |
| Publisher | King's College London (University of London) |
| Source Sets | Ethos UK |
| Detected Language | English |
| Type | Electronic Thesis or Dissertation |
| Source | https://kclpure.kcl.ac.uk/portal/en/theses/jakstat-pathway-in-the-control-of-mycobacterial-infections(cb788a0d-1c53-4f5c-8513-64c8cb50e08e).html |
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