Making sense of how Leishmania detect changes in pH and temperature (360G-Wellcome-226513_Z_22_Z)

Organisms must continually respond to changing environmental cues for survival. An extreme example are parasites transmitted between ecto- (insect vector) and endothermic (mammalian host) organisms, such as Leishmania, encountering dynamic changes including pH and temperature to which they must sense and adapt rapidly. Orthology from other organisms (G-protein coupled receptors and receptor tyrosine kinases) is absent in Leishmania and therefore little is known about how they sense and transmit these environmental cues, but protein kinases have an important role. These will be my focus in an aim to uncover how Leishmania detects pH and temperature change. I have used a kinome-wide deletion library to identify two Leishmania (haptomonad stage) differentiation kinases (HDK1 and HDK2), required in early response to decreased pH. I will resolve the HDK signalling pathway using proteomic methods and uncover kinases key to sensing increased pH and temperature change using two genetic library screens and phosphoproteomics. Additionally, I will test for a conserved role across other parasites by gene disruption in Trypanosoma cruzi. Finally, Leishmania causes a collection of debilitating and deadly diseases. As protein kinases are good drug targets, I will examine survival of mutants through the sand fly to test for transmission blocking potential.