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: 10010660
• 负责人: DAVID J BZIK
• 金额: $ 20.5万
• 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 2021-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10010660
• 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.

弓形虫弓形虫的慢性感染通常会重新激活并导致威胁生命的毒素 艾滋病或其他免疫缺陷患者的脑炎。慢性感染的分子基础 弓形虫Gondii是中枢神经系统中发展和持续的组织囊肿。消除 感染个体的囊肿会预防弓形虫性脑炎，并导致神经认知恶化 甚至在艾滋病之前，在艾滋病毒阳性个体中都会发生的功能。但是，不存在药物或其他疗法 可以瞄准慢性毒品囊肿。目前，基本生物学知识存在赤字 关于控制，维护和重新激活的寄生虫和宿主生物学 弓形虫囊肿。我们假设与腔内的密集颗粒（GRA）蛋白 网络（IVN）膜系统在操纵宿主CD8+ T细胞反应中发挥着生物学作用 控制慢性感染，以及生物学作用，包括A的结构，信号传导或感应成分 影响囊肿发展的膜系统，囊肿的维持和重新激活 囊肿。我们的慢性感染中IVN相关GRA蛋白双重作用的这一假设得到了我们的支持 初步数据。该探索性R21提案将调查IVN GRA在囊肿发展中的作用， 维护和重新激活（AIM 1），并在操纵确定的宿主CD8+ T细胞反应时 囊肿是否保持，清除或重新激活（AIM 2）。我们预计这些高影响研究将 扩展我们对调节囊肿开发，维护和的生物学的基本知识 重新激活，因此可以建立一个可以消除慢性的干预措施的分子基础 弓形虫弓形虫感染。