Toxoplasma gondii grows in the cell within a unique parasite-modified compartment, the parasitophorous vacuole (PV). The PV is separated from the host cytoplasm by the parasitophorous vacuole membrane (PVM). A morphologically distinctive feature of the PVM is its intimate association with host mitochondria and endoplasmic reticulum (ER). PVM-mitochondrial association is mediated by the rhoptry derived, PVM-localizing proteins of the ROP2 family. The intimate association of mitochondria and the PVM suggests an important function in parasite biology. Recent evidence indicates that T. gondli infected cells are profoundly resistant to apoptosis. Mitochondria play a central role in the transmission and execution of apoptotic stimuli.
The aim of this proposal is to identify the molecular basis of the blockade of host apoptosis by T. gondii. Given the importance of mitochondria in apoptosis, the role of PVM-mitochondrial association in the block of apoptosis will be examined. Apoptotic signals are transmitted and executed by a family of cysteine proteases called caspases. The effect of T. gondii infection on caspase activation and activity will be examined using biochemical approaches. Finally, the parasite mediator(s) of the blockade of host apoptosis will be identified using a combination of genomic, biochemical and genetic approaches. The genetic approach employs a novel screen to identify and isolate T. gondii mutants based on their inability to protect the infected cell from apoptotic stimuli. Identifying the molecular basis of the T. gondii mediated blockade of apoptosis will reveal novel insights into the manipulation of host functions by this fascinating parasite.
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