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Role of amylopectin granules in chronic toxoplasmosis, an HIV-AIDS defining infection

支链淀粉颗粒在慢性弓形体病（一种 HIV-AIDS 感染）中的作用

基本信息

批准号：
10025481
负责人：
ANTHONY P. SINAI
金额：
$ 19.13万
依托单位：
UNIVERSITY OF KENTUCKY
依托单位国家：
美国
项目类别：
财政年份：
2020
资助国家：
美国
起止时间：
2020-03-05 至 2022-02-28
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10025481
关键词：
Acquired Immunodeficiency Syndrome Acute Address Amylopectin Anabolism Apicomplexa Biochemical Biochemistry Biological Biology Characteristics Charge Chemicals Chronic Chronic Phase Clinical Cyst Cytoplasmic Granules Development Disease Energy-Generating Resources Enzymes Event Future Genome Glucans Glucose Glucose-6-Phosphate Glutamine Glycogen Glycogen (Starch) Synthase Growth HIV Human Immune system Immunosuppression Individual Infection Kinetics Knock-out Laboratories Length Link Location Maintenance Mediating Metabolism Morphology Parasites Parasitic infection Pharmaceutical Preparations Phase Phosphorylation Physiological Plants Play Polymers Population Process Production Publishing Regulation Resources Role Signal Transduction Starch Testing Therapeutic Intervention Tissues Toxoplasma Toxoplasma gondii Toxoplasmosis Uridine Diphosphate Sugars Work acute infection asexual chronic infection crystallinity glucose 1 phosphate imaging approach in vivo insight knock-down metabolomics mutant novel quantitative imaging sugar nucleotide tool transmission process

项目摘要

Project Summary A distinguishing characteristic of tissue cyst forming Apicomplexa, like Toxoplasma gondii, is the accumulation of amylopectin (starch) granules (AG) within bradyzoites and their absence within the actively growing tachyzoite forms. As polymers of glucose, AG functions as a battery serving as a reserve for energy production and biosynthetic functions. Our recent work established that bradyzoites retain significant replicative potential within tissue cysts in vivo. Notably, most bradyzoite replication within tissue cysts occurs asynchronously with clustered bursts of growth interceded with non-replicative periods. While the specific signals triggering these bursts remain unknown, what is clear is that they would require substantial energy and metabolite inputs to execute. Historical evidence and our findings reveal that AG levels within encysted bradyzoites are highly variable with clusters of parasites lacking AGs adjacent to others that are loaded with starch. This suggests that AG metabolism involving both synthesis and turnover are active within tissue cysts and may play a central role in the progression of chronic toxoplasmosis. We will directly address the dynamics and biological contributions of AGs in the progression of the chronic infection at the level of individual bradyzoites using novel tools and concepts developed in our recently published work. The variable levels of AG, within encysted bradyzoites, suggest that both AG accumulation and depletion are under regulatory control. Indeed the enzymatic machinery required for both the synthesis and regulated turnover of starch are encoded in the Toxoplasma genome. We will directly test the importance of AG in the acute infection, the regulation of stage conversion and the establishment/ progression of the chronic infection by targeting the commitment enzyme for starch synthesis, the UDP-glucose pyrophosphorylase (TgUDP-GPP, TgME49_218200), and the starch synthase (TgSS, TgME49_222800). Recent evidence suggests that despite being morphologically (though not biochemically) detectable, amylopectin may play a role in tachyzoite intermediary metabolism as well. In addition, the contribution of AG's to reactivation, the primary trigger of symptomatic disease in HIV-AIDS will be addressed in the context of induced immune suppression. With the proposed studies we aim to dissect the previously unexplored role of AG in tachyzoites, as factors in tachyzoite to bradyzoite conversion, the progression of the chronic infection and clinically critical reactivation in vivo. These studies will establish the groundwork for targeting AG metabolism for therapeutic intervention in the chronic infection where the paucity of effective drugs remains a significant issue in the clinical context of HIV-AIDS.

项目总结