Characterisation of molecules controlling the initiation of host cell invasion
A model for activation of invasion in Toxoplasma. A. Host cell recognition first occurs by a unknown parasite receptor. Upon binding, proteins analogous to heterotrimeric G proteins are activated and released, which then bind and sequester phospholipase C (PLC) to the membrane. B. PLC then hydrolyses the plasma membrane phosphoinositide PIP2 to DAG and soluble IP3. C. The phosphoinositide IP3 then can activate the IP3 Receptor (IP3R) to release calcium from the endoplasmic reticulum. D. Cytoplasmic calcium then activates calcium and calmodulin-dependent protein kinases. E. Phosphorylation by these kinases activates substrates to ultimately release micronemes (which contain high affinity host cell receptors) and activate the actin-myosin-based invasion motor.
Intracellular calcium signal transduction events modulate several steps leading to host cell invasion. We are looking at several molecules that we believe are involved in this process in Toxoplasma. These include a group of protein kinases that are novel to apicomplexa and that represent excellent drug targets. Further, we have evidence that suggests that phosphoinositide signaling events modulate invasion and are one of the first signals that initiate host cell invasion.