Molecular Basis of Human Toxoplasmosis

人类弓形虫病的分子基础

• 批准号: 10557864
• 负责人: L. David Sibley
• 金额: $ 66.82万
• 依托单位: WASHINGTON UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-02-15 至 2025-02-28
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10557864
• 关键词: Accidents; Acquired Immunodeficiency Syndrome; Animals; Antibiotics; Area; Attenuated; Back; Binding; Cell Death; Cell Nucleus; Cells; Central Nervous System; Chromatin; Chromatography; Complex; Cryoelectron Microscopy; Cyst; Frequencies; Funding; Future; Gene Expression; Genes; Genetic; Genetic Transcription; Growth; HIV/AIDS; Hematopoietic; High Prevalence; Highly Active Antiretroviral Therapy; Host Defense; Human; Immune; Immune response; Immune signaling; Immune system; Immunity; Immunocompromised Host; In Vitro; Individual; Infection; Inflammatory; Interferon Type II; Interferon-beta; Interferons; Mediating; Mediator; Molecular; Natural Immunity; Natural Killer Cells; NuRD complex; Nutrient Depletion; Opportunistic Infections; Parasite Control; Parasites; Pathogenicity; Pathway interactions; Patients; Process; Production; Proteins; Repressor Proteins; Research Design; Risk; Rupture; STAT1 gene; Signal Transduction; T-Lymphocyte; Testing; Tissue Survival; Tissues; Toxoplasma gondii; Toxoplasmosis; Transcription Repressor; Up-Regulation; Vacuole; Virulence; X-Ray Crystallography; Zoonoses; acute infection; adaptive immunity; base; cell type; chronic infection; cytokine; differential expression; dimer; domain mapping; effective intervention; improved; in vivo; inhibitor; mutant; prevent; protein protein interaction; recruit; transcription factor; virtual

PROJECT SUMMARY/ABSTRACT Toxoplasma gondii is a common parasite of animals and frequent cause of accidental infection in humans. Acute infections are generally controlled by the immune response, but persistent chronic infection ensues due to survival of semi-dormant stages called bradyzoites that reside within tissue cysts. In immunocompromised patients, rupture of the tissue cysts releases bradyzoites that can convert back to rapidly replicating tachyzoites, a process that goes unrestricted due to decreased T-cell immunity. The potential for reactivation presents a continued risk to immunocompromised patients due to the fact that neither the immune system nor antibiotics can eradicate chronic infections. As such, there is still a need to understand fundamental mechanisms of pathogenicity in order to develop more effective interventions. One of the key mediators of innate and adaptive immunity to T. gondii is the production of interferons that activate cells to control the parasite through a variety of mechanisms including nutrient depletion, targeting the parasitophorous vacuole for destruction, or growth inhibition. As one of the world's most successful parasites, it is not surprising that T. gondii has developed active mechanisms to block these immune control pathways. Our studies seek to define the molecular bases of how T. gondii blocks or subverts interferon signaling to overcome host defenses. In the prior funding period, we identified a secretory parasite protein that traffics to the host nucleus where it binds to the transcription factor STAT1 and recruits a chromatin modifying complex to block gene expression induced by both type I (IFN-β) and type II (IFN-γ) interferons. Our prior studies demonstrate that the ability of the parasite to block type II IFN is primarily important in the acute infection while its ability to subvert type I IFN is key in the central nervous system during chronic infection. We have also recently identified a second secreted effector that also traffics to the host cell nucleus and blocks the type I IFN pathway. The proposed studies will explore the molecular mechanisms by which these effectors inhibit IFN signaling by bradyzoites and thus assure survival of tissue cysts that are responsible for chronic infection.

项目总结/摘要 弓形虫是一种常见的动物寄生虫，也是人类意外感染的常见原因。 急性感染通常由免疫反应控制，但持续的慢性感染会导致 半休眠阶段的生存称为缓殖子，居住在组织囊肿。在免疫功能低下 患者，组织囊肿破裂释放缓殖子，可以转换回快速复制 速殖子，一个由于T细胞免疫力下降而不受限制的过程。重新激活的可能性 对免疫功能低下的患者存在持续的风险，因为免疫系统和 抗生素可以根除慢性感染。因此，仍然需要了解基本的 致病机制，以制定更有效的干预措施。的关键调解人之一 对T.弓形虫是生产干扰素，激活细胞，以控制 寄生虫通过各种机制，包括营养耗尽，针对寄生虫液泡 用于破坏或抑制生长。作为世界上最成功的寄生虫之一，T。 弓形虫已发展出阻断这些免疫控制途径的主动机制。我们的研究试图定义 T.弓形虫阻断或破坏干扰素信号以克服宿主防御。在 在前一个资助期，我们发现了一种分泌型寄生虫蛋白，它可以运输到宿主细胞核，在那里它可以结合到 转录因子STAT1并募集染色质修饰复合物以阻断诱导的基因表达 I型（IFN-β）和II型（IFN-γ）干扰素。我们先前的研究表明， 寄生虫阻断II型IFN在急性感染中主要是重要的，而其破坏I型IFN的能力是重要的。 在慢性感染期间中枢神经系统的关键。我们最近还发现了第二种分泌的 也运输到宿主细胞核并阻断I型IFN途径的效应物。拟议的研究将 探索这些效应物通过缓殖子抑制IFN信号传导的分子机制， 确保导致慢性感染的组织囊肿的存活。