One of the most remarkable features of the obligate intracellular parasite, Toxoplasma gondii, is its ability to infect almost any nucleated cell in an extremely broad host range. During asexual growth in such cells, the parasite can adopt either of two forms: the rapidly dividing tachyzoite and the more slowly growing encysted form, the bradyzoite. This application addresses the molecular basis of the interaction between the tachyzoite form and the individual host cells in which it resides. Key to this interaction are a set of highly specialized secretory organelles known as rhoptries. These club-shaped structures are found at the apical end of all members of the Apicomplexa, including the causative agent of human malaria, Plasmodium. The rhoptries release their contents when these parasites invade into a host cell and this release appears key to both the physical act of invasion as well as to the co-opting of host cell functions once the parasite is inside. Recent work has shown that rhoptry neck proteins (RONs) help create the ring of physical contact between the host cell and invading parasite, the so-called moving junction. Rhoptry bulb proteins (ROPs), on the other hand appear to function within the cytosol/nucleus of the infected cell as well as on the parasitophorous vacuole that surrounds the dividing parasites. The work described in this application will determine how key RONs and ROPs perform their critical functions including identification of their location and topology and the host pathways/proteins with which they interact. The relevance of particular ROP functions to the interaction with the host as a whole will also be determined.
Toxoplasma gondii is a single-celled parasite of many warm-blooded animals, including humans in whom it can cause severe infection of the central nervous system. Disease is most serious in the developing fetus and in persons who are immunocompromised by HIV/AIDS or other circumstances (lymphoma patients, transplant recipients, etc.). Our work will shed light on how this parasite infects and ultimately takes over a human cell.
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