Glucosylation Regulates Cyst Wall Formation, Stability, and Persistence of the AIDS Pathogen Toxoplasma gondii

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Infection by Toxoplasma gondii [Toxoplasma] is a common cause of focal central nervous system (CNS) disease in AIDS. During AIDS associated immune suppression, Toxoplasma cysts reactivate in the central nervous system (CNS) and this reactivation causes a debilitating and life-threatening Toxoplasmic encephalitis. In addition, HIV+ and AIDS patients chronically infected with Toxoplasma cysts experience accelerated deteriorating neurocognitive function. The biological basis of Toxoplasma caused disease in the CNS of HIV+ and AIDS patients is the chronic stage cyst structure that resists clearance by host immunity and maintains the viability of infectious bradyzoite stage parasites in the CNS. There currently is no therapy that can eliminate Toxoplasma cysts or prevent their reactivation and there is a significant gap in basic knowledge concerning the biology that underpins cyst persistence and cyst reactivation, particularly in HIV/AIDS and immune suppressed patients. We hypothesize that formation, stability, persistence, and reactivation of chronic stage cysts in AIDS immune suppression is dependent on an uncharacterized ~48 kDa N-acetylglucosamine modified glucosylated major cyst wall protein that binds the chitin-binding lectin succinylated wheat germ agglutinin (sWGA). The goal of this high impact exploratory R21 project is to identify the major sWGA binding glucosylated cyst wall protein(s) (Aim 1), and to conduct a series of experiments to test the hypothesis that the major glucosylated cyst wall protein is crucial for cyst wall formation, stability, persistence, and the reactivation of cysts in the CNS during AIDS defining immune suppression (Aim 2). This research is significant because O-linked sugar modification of the major cyst wall protein CST1 is known to underpin mechanisms of cyst stability, and CST1 co-localizes with the major cyst wall glucosylated protein(s). This co-localization supports the premise and hypothesis that cyst wall glucosylation supports cyst stability, and therefore cyst persistence and the ability to reactivate during AIDS. Thus, understanding how glucosylation of the cyst wall impacts cyst stability, persistence, and reactivation will further advance our basic understanding of the importance of cyst wall sugar modifications in the context of HIV/AIDS immune deficiency.