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

基本信息

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
项目类别：
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

项目摘要

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.

弓形虫慢性感染通常会重新激活并导致危及生命的弓形虫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是在中枢神经系统中发育并持续存在的组织囊肿。消除感染者体内的包囊可以预防弓形虫脑炎以及神经认知能力的恶化 HIV 阳性个体甚至在艾滋病发生之前就发生了这种功能。然而，不存在药物或其他疗法可以针对慢性弓形虫囊肿。目前，基础生物学知识匮乏关于控制发育、维持和重新激活的寄生虫和宿主生物学弓形虫包囊。我们假设与液泡内相关的致密颗粒（GRA）蛋白网络（IVN）膜系统在操纵宿主 CD8+ T 细胞反应中发挥生物学作用，控制慢性感染，以及作为结构、信号或传感成分的生物学作用影响囊肿发育、囊肿维持和重新激活的膜系统囊肿。 IVN 相关 GRA 蛋白在慢性感染中具有双重作用的这一假设得到了我们的支持初步数据。这项探索性 R21 提案将研究 IVN GRA 在囊肿发育中的作用，维持和重新激活（目标 1），以及操纵决定宿主 CD8+ T 细胞反应囊肿是否得到维持、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展我们调节囊肿发育、维持和生长的生物学基础知识重新激活，因此可能为根除慢性病的干预措施奠定分子基础弓形虫感染。