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: 10493386
• 负责人: DAVID J BZIK
• 金额: $ 24.74万
• 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 2024-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10493386
• 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.

弓形虫感染是引起中枢神经系统疾病的常见原因 艾滋病在艾滋病相关的免疫抑制期间，弓形虫包囊在中枢神经系统中重新激活， 系统（CNS），这种再激活导致衰弱和危及生命的弓形虫脑炎。在 此外，HIV+和艾滋病患者慢性感染弓形虫囊肿的经历加速 神经认知功能恶化弓形虫致HIV+中枢神经系统疾病的生物学基础 和艾滋病患者是慢性阶段的囊肿结构，它抵抗宿主免疫的清除，并保持 感染性缓殖子期寄生虫在CNS中的生存能力。目前还没有一种治疗方法可以消除 弓形虫包囊或防止其再激活，在有关弓形虫包囊的基本知识方面存在重大差距。 支持囊肿持续存在和囊肿再激活的生物学，特别是在HIV/AIDS和免疫抑制中 患者我们推测艾滋病慢性期囊肿的形成、稳定、持续和再激活 免疫抑制依赖于未表征的~48 kDa N-乙酰葡糖胺修饰的葡萄糖基化 结合几丁质结合凝集素琥珀酰化小麦胚芽凝集素（sWGA）的主要囊壁蛋白。目标 这个高影响力的探索性R21项目的目的是鉴定主要的sWGA结合糖基化囊壁蛋白 (Aim 1），并进行了一系列的实验，以检验假设，主要是糖基化的囊壁 蛋白质是至关重要的囊肿壁的形成，稳定性，持久性，并重新激活囊肿在中枢神经系统中， 艾滋病定义免疫抑制（目标2）。这项研究是有意义的，因为O-连接糖修饰的 已知主要的囊壁蛋白CST 1支持囊稳定性的机制，并且CST 1与 主要的囊壁糖基化蛋白。这种共定位支持的前提和假设， 壁葡糖基化支持囊肿的稳定性，并因此支持囊肿的持久性和在AIDS期间重新激活的能力。 因此，了解囊壁的糖基化如何影响囊的稳定性、持久性和再活化， 进一步推进我们对囊壁糖修饰的重要性的基本理解， 艾滋病毒/艾滋病免疫缺陷。