Role of NFKB in resistance to Toxoplasma gondii

NFKB在抵抗弓形虫中的作用

• 批准号: 6510923
• 负责人: CHRISTOPHER A HUNTER
• 金额: $ 23.78万
• 依托单位: UNIVERSITY OF PENNSYLVANIA
• 依托单位国家: 美国
• 财政年份: 2001
• 资助国家: 美国
• 起止时间: 2001-03-01 至 2006-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6510923
• 关键词: CD28 molecule; Retroviridae; T lymphocyte; Toxoplasma gondii; biological signal transduction; bone marrow; cell differentiation; cell proliferation; cellular immunity; dendritic cells; gene targeting; genetically modified animals; immunoregulation; interferon gamma; interleukin 12; laboratory mouse; natural killer cells; nuclear factor kappa beta; opportunistic infections; parasite infection mechanism; protein structure function; tissue /cell culture; toxoplasmosis; transfection /expression vector

DESCRIPTION: The overall aim of this proposal is to understand the role of NF-kB in the regulation of the immune response to Toxoplasma gondii. T. gondii is an opportunistic pathogen in patients with acquired and primary deficiencies in cell mediated immunity. Resistance to this pathogen is based on the production of IL-12 which is required for NK and T cell production of IFN-g the major mediator of resistance to T. gondii. The NF-icB proteins are a family of transcription factors associated with many of the events that lead to the production of IFN-g required for resistance to T. gondii. For example, NF-icB is associated with the production of IL-12, and the ability of IL-12 to stimulate the production of IFN-'y is dependent on co-factors, such as IL-18 and CD28, which activate NF-kB. Thus, NF-kB is likely to be involved in resistance to T. gondii. Our studies have shown that infection with T. gondii leads to activation of NF-icB and that two members of this family, c-Rel and Rem, are required for optimal production of IFN-g. Additional studies using a transgenic mouse which expresses a specific inhibitor of NF-icB in 'I cells, indicates that the activation of NF-kB in I cells is required for the development of protective IFN-g responses. Based on these preliminary studies, we propose to perform studies which address the molecular and cellular basis for the role of NF-kB in the development of IFN-g responses. The proposed studies will not only provide a mechanism for why mice deficient in NF-kB mediated signaling are susceptible to toxoplasmosis, but will also provide novel insights into the mechanisms that lead to the production of IFN-g, a cytokine critical for resistance to many of the opportunistic infections which affect patients with AIDS.

描述：该提议的总体目的是了解 NF-KB在调节对弓形虫的免疫反应中。 T. Gondii 是获得性和原发性缺陷患者的机会性病原体 在细胞介导的免疫力中。对这种病原体的抗性是基于 IL-12的生产是IFN-G的NK和T细胞产生所必需的 对弓形虫的抗性的主要介体。 NF-ICB蛋白是一个家庭 与许多导致许多事件相关的转录因子 抗gondii抗性所需的IFN-G。例如，NF-ICB 与IL-12的产生以及IL-12的能力有关 刺激IFN-YY的产生取决于副因素，例如IL-18 和CD28，它激活NF-KB。因此，NF-KB可能参与 对T. gondii的抵抗力。我们的研究表明，Gondii的感染 导致NF-ICB的激活以及该家族的两个成员C-Rel和 REM是最佳生产IFN-G所需的。使用A的其他研究 转基因小鼠在'I细胞中表达NF-ICB的特定抑制剂， 表明I细胞中NF-KB的激活是需要的 开发保护性IFN-G响应。基于这些初步研究， 我们建议进行针对分子和细胞基础的研究 对于NF-KB在IFN-G反应的发展中的作用。提议 研究不仅将提供一种机制，以说明为什么小鼠缺乏NF-KB 介导的信号传导容易受到弓形虫病的影响，但也将提供 对导致IFN-G产生的机制的新颖见解，一个 细胞因子对于对许多机会感染的抵抗至关重要 影响艾滋病患者。