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

糖基化调节艾滋病病原体弓形虫的囊壁形成、稳定性和持久性

• 批准号: 10334999
• 负责人: DAVID J BZIK
• 金额: $ 22.24万
• 依托单位: DARTMOUTH COLLEGE
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-09-22 至 2023-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10334999
• 关键词: AIDS/HIV problem; Acetylgalactosamine; Acquired Immunodeficiency Syndrome; Acute; Address; Affect; Agglutinins; Binding; Binding Proteins; Biological; Biology; Brain; CCL7 gene; Cells; Centers for Disease Control and Prevention (U.S.); Central Nervous System Diseases; Cessation of life; Chitin; Chitinase; Chronic; Clinical Management; Cyst; Cytoplasmic Granules; Data; Development; Diagnosis; Disease; Dolichos; Exhibits; Genetic; Giardia; Goals; HIV; Hospitalization; Immune; Immunity; Immunosuppression; In Vitro; Individual; Infection; Knowledge; Lectin; Life; Link; Measures; Mediating; Membrane; Modification; Molecular; Morbidity - disease rate; Mucins; Mus; Neuraxis; Neurocognitive; Neurocognitive Deficit; Oocysts; Oral Ingestion; Parasites; Patients; Permeability; Phenotype; Polymers; Population; Proteins; Proteome; Proteomics; Research; Series; Stains; Structure; Testing; Thick; Thinness; Toxoplasma; Toxoplasma gondii; Toxoplasmosis; Tropism; United States; burden of illness; chronic infection; co-infection; experience; experimental study; foodborne pathogen; in vivo; mechanical force; mortality; pathogen; prevent; succinylated wheat germ agglutinin; sugar; therapy development; toxoplasmic encephalitis; web site

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.

弓形虫感染是局灶性中枢神经系统 (CNS) 疾病的常见原因 在艾滋病方面。在艾滋病相关的免疫抑制期间，弓形虫包囊在中枢神经中重新激活 系统（CNS），这种重新激活会导致使人衰弱并危及生命的弓形虫脑炎。在 此外，长期感染弓形虫包囊的 HIV+ 和艾滋病患者的感染速度加快 神经认知功能恶化。弓形虫引起 HIV+ 中枢神经系统疾病的生物学基础 艾滋病患者是慢性期囊肿结构，它抵抗宿主免疫的清除并维持 中枢神经系统中传染性缓殖子阶段寄生虫的生存能力。目前尚无治疗方法可以消除 弓形虫包囊或防止其重新激活，并且有关弓形虫包囊的基础知识存在显着差距 支持囊肿持久性和囊肿再激活的生物学，特别是在艾滋病毒/艾滋病和免疫抑制中 患者。我们假设艾滋病慢性期囊肿的形成、稳定性、持续性和重新激活 免疫抑制依赖于未表征的~48 kDa N-乙酰氨基葡萄糖修饰的葡萄糖基化 主要囊壁蛋白，与几丁质结合凝集素琥珀酰化麦芽凝集素 (sWGA) 结合。目标 这个具有高影响力的探索性 R21 项目的目的是确定主要的 swGA 结合糖基化囊壁蛋白 （目标1），并进行一系列实验来检验主要糖基化囊壁的假设 蛋白质对于中枢神经系统囊肿壁的形成、稳定性、持久性和重新激活至关重要。 艾滋病定义了免疫抑制（目标 2）。这项研究意义重大，因为 O-连接糖修饰 已知主要的囊壁蛋白 CST1 是囊肿稳定性机制的基础，并且 CST1 与 主要囊壁糖基化蛋白。这种共定位支持了囊肿的前提和假设 壁糖基化支持囊肿稳定性，因此支持囊肿持久性和艾滋病期间重新激活的能力。 因此，了解囊肿壁的糖基化如何影响囊肿的稳定性、持久性和重新激活将有助于 进一步推进我们对囊壁糖修饰重要性的基本理解 艾滋病毒/艾滋病免疫缺陷。