Intravacuolar network dense granule protein biology in chronic Toxoplasma infection

慢性弓形虫感染中的液泡内网络致密颗粒蛋白生物学

• 批准号: 10084815
• 负责人: DAVID J BZIK
• 金额: $ 24.6万
• 依托单位: DARTMOUTH COLLEGE
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-01-13 至 2022-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10084815
• 关键词: Acquired Immunodeficiency Syndrome; Affect; Antigen Presentation; Antigens; Biological; Biological Assay; Biology; CD8-Positive T-Lymphocytes; Cells; Central Nervous System Cysts; Cessation of life; Chronic; Clinical Management; Competence; Complement; Cyst; Cytoplasmic Granules; Data; Development; Diagnosis; Electron Microscopy; Epitopes; Genetic; HIV Seropositivity; Histocompatibility; Hospitalization; Immune; Immune response; Inbred BALB C Mice; Individual; Infection; Intervention; Knowledge; Life; Maintenance; Measures; Mediating; Membrane; Molecular; Mus; N-terminal; Neuraxis; Neurocognitive; Neurons; Oocysts; Oral; Oral Ingestion; Parasites; Patients; Pattern; Pharmaceutical Preparations; Play; Population; Proteins; Proteomics; Resistance; Role; Signal Transduction; Structure; System; T cell response; Testing; Tissues; Toxoplasma; Toxoplasma gondii; Toxoplasmosis; United States; Vacuole; antigen binding; antiretroviral therapy; cell type; chronic infection; foodborne pathogen; in vitro Assay; microscopic imaging; mutant; novel; oral infection; prevent; toxoplasmic encephalitis

Chronic infection with Toxoplasma gondii will often reactivate and cause life-threatening Toxoplasmic encephalitis in patients with AIDS or other immune deficiencies. The molecular basis of chronic infection with Toxoplasma gondii is the tissue cyst that develops and persists in the central nervous system. The elimination of cysts in infected individuals would prevent Toxoplasmic encephalitis, as well as deteriorating neurocognitive function that occurs in HIV-positive individuals even prior to AIDS. However, no drug or other therapy exists that can target the chronic Toxoplasma cyst. Currently, there is a deficit in fundamental biological knowledge regarding parasite and host biology that controls the development, maintenance, and reactivation of Toxoplasma cysts. We hypothesize that dense granule (GRA) proteins that associate with the intravacuolar network (IVN) membrane system play biological roles in manipulating the host CD8+ T cell responses that control chronic infection, as well as biological roles as structural, signaling, or sensing components of a membrane system that influences the development of cysts, the maintenance of cysts, and the reactivation of cysts. This hypothesis for a dual role for IVN associated GRA proteins in chronic infection is supported by our preliminary data. This exploratory R21 proposal will investigate the role of IVN GRAs in cyst development, maintenance and reactivation (Aim 1), and in manipulating the host CD8+ T cell responses that determine whether cysts are maintained, cleared, or reactivated (Aim 2). We anticipate these high impact studies will expand our fundamental knowledge of the biology that regulates cyst development, maintenance, and reactivation, and may therefore establish a molecular basis for an intervention that can eradicate chronic Toxoplasma gondii infection.

慢性感染弓形虫后，常可重新激活并引起危及生命的弓形虫感染。 艾滋病或其他免疫缺陷患者的脑炎。慢性感染的分子基础 刚地弓形虫是一种在中枢神经系统中发展并持续存在的组织囊肿。消除 感染者的囊肿可以预防弓形虫脑炎，以及神经认知功能的恶化。 甚至在艾滋病发生之前，HIV阳性个体也会发生这种功能。然而，没有药物或其他疗法存在 可以针对慢性弓形虫囊肿目前，基础生物学知识不足， 关于寄生虫和宿主生物学，控制发展，维护和重新激活 弓形虫包囊。我们推测，与液泡内蛋白相关的致密颗粒（GRA）蛋白， 网络（IVN）膜系统在操纵宿主CD8+ T细胞应答中发挥生物学作用， 控制慢性感染，以及作为结构，信号或传感组件的生物学作用， 膜系统，影响囊肿的发展，囊肿的维持，和重新激活， 囊肿IVN相关GRA蛋白在慢性感染中的双重作用的假设得到了我们的支持。 初步数据。这项探索性的R21提案将研究IVN GRA在囊肿发育中的作用， 维持和再活化（目的1），并在操纵宿主CD8+ T细胞反应，决定 囊肿是否被维持、清除或重新激活（目标2）。我们预计这些高影响力的研究将 扩大我们的生物学的基本知识，调节囊肿的发展，维护， 激活，并因此可能建立一个干预的分子基础，可以根除慢性 弓形虫感染。