The protozoan parasite Toxoplasma gondii is an important human and veterinary pathogen. In humans, acute disease is caused by rapidly growing 'tachyzoites'while chronic diseases is caused by latent 'bradyzoite'tissue cysts;both stages are essential for disease propagation and causation. Tachyzoites are responsible for congenital birth defects and latent bradyzoites represent a continual threat to immunocompromised (AIDS) patients. The interconversion process between tachyzoites and bradyzoites is central to the parasite's survival and pathogenicity, yet it remains poorly understood. Several lines of evidence have linked chromatin remodeling with parasite development into bradyzoite cysts, but the fundamental units of chromatin - histones - remain to be characterized in this important parasite. Our preliminary results show that T. gondii has a canonical H2A as well as two H2A variants (H2AX and H2AZ). In addition, it has a canonical H2B and H2B variant (H2Bv). The H2A and H2B class of histones and histone variants in T. gondii are unusual in sequence composition and how they interact. Thus a major gap in our knowledge is how T. gondii nucleosomes are structured and post-translationally modified in the different stages of the parasite.
In specific aim 1 we will determine the configuration of H2A and H2B histones in T. gondii nucleosomes and will analyze nucleosome composition of active and silent chromatin during bradyzoite development.
In specific aim 2 we will identify non-histone proteins associating with T. gondii H2As and H2Bs histones during in both tachyzoites and bradyzoites. Determination of the non-histone proteins that associate with these histone variants is essential to learn more about the function of these histones in parasite physiology, and will illuminate the key proteins regulating the reading and writing of the Toxoplasma histone code.
In specific aim 3, we will construct a post-translational modification map of T. gondii H2As and H2Bs histones in the different parasite stages. Given the sequence disparity and unusual variants in the T. gondii histone classes, it is important to identify the post-translational modifications on these histones during tachyzoite and bradyzoite stages.
Toxoplasma gondii has achieved notoriety as a cause of life-threatening opportunistic disease in immunocompromised individuals. In addition, with the growing threat of bioterrorism this parasite is now listed as a Category B pathogen in the NIH/CDC list of priority pathogens. The proposal will produce a significant impact in elucidating the genetic basis and mechanisms underlying development in Toxoplasma parasites with a great potential of identifying novel drug targets against toxoplasmic chronic infection
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