Host nutrient uptake and regulation by Toxoplasma

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DESCRIPTION (provided by the applicant): Current treatments for the control of Toxoplasma gondii infections require long-term medication fraught with side effects and they are ineffective against the long-lived encysted stage, which is responsible for life threatening acute toxoplasmosis in immunocompromised individuals. The need for identifying novel drug targets is imperative. T. gondii is an obligate intracellular parasite, residing in a vacuole that is extensively modified by parasite secretions. It is speculated that the vacuolar parasite-induced modifications are largely for the purpose of nutrient uptake. However, essentially nothing is known about the nutritional needs of T. gondii. The strategies employed by Toxoplasma to access host nutrients and to regulate their supply will be characterized by using genomic, morphological, biochemical and genetic approaches. Host microtubules extend into the vacuolar space and induce the delivery of host lysosomes containing nutrients. The tubules mediating the lysosome delivery are then stabilized by the formation of a protein coat secreted by the parasite. A first aim of the proposal will focus on the molecular machinery underlying the reorganization of host microtubules around the Toxoplasma vacuole. The nature of the proteins forming the coat and their role in host lysosome scavenging into the vacuole will be studied. The primary source of T. gondii sterol is from lipoprotein uptake, a process that is specifically increased in infected cells. A second aim will address the alterations in cholesterol homeostasis in T. gondii-infected cells as well as the regulatory mechanisms developed by T. gondii to optimize cholesterol acquisition into proper organelles. The long-term goal of these studies is to reveal specificities in the pathways of nutrient acquisition which may offer opportunities for selective therapeutic intervention or to usurp these pathways for drug delivery. Simultaneously, this project is of broad cell biology interest and may provide insight into cholesterol homeostasis, microtubule dynamics and the mechanisms of membrane deformation in mammalian cells.