Active Infection & Immunity Cells, Biochemistry & Physiology

Making sense of how Leishmania detect changes in pH and temperature

Funder Wellcome Charity-funded
Recipient organisation University of York
Funding £2.3M
Period Jun 2023 — Feb 2032

In plain English

AI plain-English summary

Leishmania parasites must sense a sudden drop in pH and a rise in temperature as they move from a sand fly’s gut into a human’s bloodstream, but no one knows how they detect these changes. The problem is that Leishmania lack the usual molecular sensors—like G-protein coupled receptors—that other organisms use to read their environment. This project aims to find the protein kinases that act as the parasite’s thermometers and pH meters. The researcher has already identified two kinases, HDK1 and HDK2, that respond to falling pH. She will now map the full signalling pathway, screen for kinases that detect rising temperature and higher pH, and test whether similar sensors exist in the related parasite *Trypanosoma cruzi*. This is fundamental science. Understanding how Leishmania senses its surroundings could reveal new drug targets. Because protein kinases are druggable, blocking these sensors might prevent the parasite from ever adapting to the human host—stopping infection before it starts. The researcher will also test whether mutant parasites that cannot sense pH survive inside sand flies, which could point toward a transmission-blocking strategy. If successful, this work would open a completely new route for treating leishmaniasis, a neglected disease that causes disfiguring skin ulcers and fatal organ damage.

View original technical description
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.

View the original record at the funder ↗

Researchers

Nicola Baker (EPMC Awardee)

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Original classification

Career Development Award

Plain English summaries and category classifications on this site are generated by AI and may not perfectly reflect the original research.