Signalling in malaria parasites
Malaria is a mosquito-borne infectious disease caused by Plasmodium spp. parasites. During their journey between humans and the mosquito vector, Plasmodium parasites face extremely diverse environments, from the warmth of red blood cells to the very inside of a mosquito gut. To sense and respond to changing environments, malaria parasites use a complex system of intracellular communication that relies on signalling molecules such as second messengers and protein kinases. Ca2+ signalling has received much attention in research on malaria parasites as it has important functions in symptomatic asexual blood stages, the preceding liver-stage infection and transmission through the mosquito. However, malaria parasites are much diverged from classical model eukaryotes and despite its importance, how Ca2+ regulates progression through the life cycle of malaria parasites remains poorly understood.
That Plasmodium is highly divergent from model organisms is illustrated by the fact that around 60% of all parasite genes are not functionally annotated. As a result computational predictions of Ca2+ signalling molecules in malaria parasites suffer from some uncertainty. Some transporters that remove Ca2+ from the cytosol in higher eukaryotes cannot be identified in Plasmodium genomes. Similarly, how Ca2+ is released from internal stores in response to intracellular signals remains a mystery in the absence of canonical receptors and regulators. Ca2+-dependent pathways also differ significantly between Plasmodium and its human host. Malaria parasites lack close homologues of Protein Kinase C and Ca2+-/calmodulin-dependent protein kinases. Instead, they use plant-like Ca2+-dependent protein kinases (CDPKs) for which no Plasmodium substrates have been identified in vivo yet. The identification of these missing links in Plasmodium Ca2+ signalling is challenging, but in addition to providing new insights into the origins of complex signalling in eukaryotes, it holds the chance to identify new drug targets to block the development of multiple parasite stages. In this context our current research aims at:
1- Identifying the molecular players underpinning Ca2+ homeostasis across the life cycle of Plasmodium parasites;
2- Understanding how Ca2+ signals are translated into appropriate physiological responses;
3- Identifying Ca2+ signalling molecules which can be targeted to block the development of the parasites.