Toxoplasma gondii is a major opportunistic pathogen that causes severe disease (toxoplasmosis) in congenitally infected babies and immunocompromised individuals such as those suffering from AIDS. Because it is an obligate intracellular parasite, T. gondii must invade a host cell to survive and replicate. Furthermore, T. gondii invasion is directly responsible for the pathology of toxoplasmosis, since subsequent intracellular replication and egress destroys the infected host cell. Thus, a better understanding of T. gondii invasion could lead to the development of treatments for toxoplasmosis based on inhibition of invasion. Our recent studies indicate that parasite secretion of organelles called micronemes is essential for T. gondii invasion. Thus, the long-term goal of this proposal is to elucidate the function of micronemal proteins in an effort to identify new potential targets for treating toxoplasmosis. We will begin by focusing on MIC2 because our studies suggest that this micronemal protein likely functions as an important adhesin for T. gondii invasion.
Specific Aim I will be to use RNA antisense inhibition to measure the importance of MIC2 for T. gondii invasion of host cells and gliding motility.
Specific Aim II will be to use deletion and site-specific mutagenesis to identify the sites on MIC2 that mediate cell adhesion.
Specific Aim III will be to identify host cell receptors recognized by MIC2. These studies will directly lead to a better understanding of the molecular mechanisms underlying T. gondii invasion of host cells.
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