application abstract): Dr. Ward`s research addresses the cell biology and molecular mechanisms of host-parasite interactions, with a primary focus on how the closely related parasites Plasmodium and Toxoplasma interact with and invade cells of their hosts. Plasmodium is the causative agent of malaria and Toxoplasma causes life-threatening disease in utero and in the immuncompromised patient. Dr. Ward`s contributions to the field include (1) defining the origin of the vacuole surrounding the intracellular parasite, (2) characterizing the mechanisms of protein trafficking within the intracellular parasite, and (3) studying the regulation of parasite actin polymerization and its role in invasion. His current focus is the identification of novel, transmembrane proteins on the surface of Toxoplasma that function in the interaction of the parasite with host cells. In preliminary work he has successfully identified at least two novel Toxoplasma surface proteins and is in the process of characterizing these proteins and identifying others. To understand the biological function of these proteins, Dr. Ward proposes to draw upon the powerful tools of Toxoplasma molecular genetics. The salary support provided by this award will enable him to have the protected research time he needs to effectively integrate molecular approaches into his research. Congenital infection with Toxoplasma can lead to disease ranging from impaired vision to hydrocephalus and death. Toxoplasma gondii also has emerged as a major opportunistic pathogen and one of the most common causes of central nervous system pathology in AIDS patients. It is estimated that 20- 47% of AIDS patients in the USA develop Toxoplasma encephalitis, which is uniformly fatal if left untreated. Dr. Ward`s long-term goal is to understand the molecular mechanisms of host cell invasion by this parasite. The identification of surface proteins that function in invasion is an important first step in this direction. In addition, new approaches are urgently needed for the diagnosis of toxoplasmosis in pregnant women and immunocompromised patients, and this proposal directly addresses this need. Finally, because invasion palays such a direct role in parasite biology and the pathology of toxoplasmosis, the identification of parasite surface molecules that mediate invasion could lead to new chemotherapeutic of vaccine- based approaches to disease control or prevention.
