Role of Amylopectin Granules in Chronic Toxoplasmosis, an HIV-AIDS Defining Infection

Grants and Contracts Details


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 contrary to the conventional wisdom, 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). In addition, the contribution of AG’s to reactivation, the primary trigger of symptomatic disease in HIV-AIDS, will be directly addressed. Here, we will establish whether T. gondii mutants unable to synthesize AG are altered with regard to the dynamics of reactivation 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. In addition to reveling new insights into parasite biology, 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.
Effective start/end date3/5/202/28/23


  • National Institute of Allergy and Infectious Diseases: $420,750.00


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