Toxoplasmosis is caused by the parasite Toxoplasma gondii. The infection of T. gondii can cause severe tissue damages when the immune system is compromised (such as in AIDS patients) or underdeveloped (such as in fetuses). If not treated in time, uncontrolled T. gondii proliferation (i.e. acute toxoplasmosis) will have devastating consequences, including the development of toxoplasmic encephalitis. Current medications for treating toxoplasmosis drugs block growth but do not kill the parasite;thus they must be taken for long periods, during which severe side-effects routinely develop. For infection with drug resistant parasite strains, the treatment options either are very limited or do not exist. New drug that target parasites more specifically are therefore desperately needed. To cause disease, T. gondii must reiterate its lytic cycle through host cell invasion, replication, and parasite egress. The successful completion of this cycle requires that the parasite sense changes in environmental conditions and switch between non-motile and motile states, accordingly. Despite its importance in parasite physiology, the signal relay that regulates this switch is poorly understood. Recently we discovered a previously unknown mechanism of regulating cell motility in T. gondii, mediated by a novel protein lysine methyltransferase, AKMT (for Apical complex lysine (K) methyltransferase). When AKMT is absent, the parasite remains immotile. Both invasion and egress, and thus the complete lytic cycle, are inhibited. If we understood the detailed nature of this inhibition, then it could be exploited to develop new parasite specific drugs. Towards that goal, three major questions need to be answered. 1) Is the motor itself crippled in the absence of AKMT? 2) Whether or not the motor is crippled, are other essential components of the motility apparatus dependent on methylation? 3) Why, in functional terms, is methylation required for each sensitive component (i.e., required for proper assembly of the apparatus?;for ATP hydrolysis or other catalytic activity?;for correct subcellular localization?) To answer these critical questions, we have designed the following three specific aims:
Aim1 -Determine if AKMT directly regulates the activity of the myosin motor complex;
Aim2 - Identify AKMT targets;
and Aim3 - Determine the function and spatial-temporal distribution of the AKMT targets. We will use a multi-faceted approach to pursue our aims, combining proteomics, state of the art imaging technologies, biophysical assays and targeted gene disruption.
Toxoplasma gondii is one of the most successful human parasites, chronically infecting ~ 20% of the total world population. The infection of T. gondii ca cause severe tissue damages when the immune system is compromised (such as in AIDS patients) or underdeveloped (such as in fetuses). Our study on the regulation of T. gondii cell movement will contribute to the rational selection of novel chemotherapeutic targets for controlling the damages caused by this parasite.
|Liu, Jun; Wetzel, Laura; Zhang, Ying et al. (2013) Novel thioredoxin-like proteins are components of a protein complex coating the cortical microtubules of Toxoplasma gondii. Eukaryot Cell 12:1588-99|
|Sivagurunathan, Senthilkumar; Heaslip, Aoife; Liu, Jun et al. (2013) Identification of functional modules of AKMT, a novel lysine methyltransferase regulating the motility of Toxoplasma gondii. Mol Biochem Parasitol 189:43-53|