Toxoplasma gondii is an important cause of focal central nervous system infections in patients with HIV, lethal infections in heart transplant patients, and devastating congenital infections of newborns. The organism is an obligate intracellular protozoan parasite, which is capable of invading and replicating in essentially all nucleated cells, and requires nutrients from the host cell to survive and replicate. The parasite resides in an unusual intracellular vacuole, which is extensively modified by secretion from parasite secretory organelles. The focus of our laboratory is to understand how these parasite-induced modifications of the vacuole contribute to the nutrient acquisition necessary for virulence. ? ? We have recently demonstrated that the parasite induces a unique process of microtubule-based invaginations from the host cell cytosol into the vacuolar space, for acquisition of nutrients internalized into the host cell via the host endocytic pathway. In particular, cholesterol internalized into the host cell via the LDL receptor is delivered to the parasite via this pathway. Cholesterol transport and metabolism by the parasite are targets for therapeutic intervention, since the organism cannot synthesize sterols de novo. ? ? In contrast, nothing is known about the biosynthetic capacity of the organism for phospholipids, nor about mechanisms for phospholipid acquisition from the host cell. These topics are readily amenable to study. For example, as one of many pieces of intriguing preliminary data, we show that extracellular parasites cannot synthesize phosphatidylcholine, the major T. gondii phospholipid, when provided with the head group precursor choline. Unlike cholesterol, this lipid should not be readily acquired from the host cell endocytic pathway, and must be accessed by another route. ? ? To elucidate a coherent scheme for phospholipid homeostasis in T. gondii, we will systematically determine 1.) Which phospholipids are synthesized by the parasite, 2.) which phospholipids are acquired from the host cell, 3.) the molecular mechanisms by which the parasite acquires needed phospholipids from the host cell. The long-term goal is to identify strategies to block T. gondii phospholipid acquisition from the host cell and thus to interfere with parasite growth.
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