C-Rel in resistance to toxoplasma gondii

C-Rel 抵抗弓形虫

• 批准号: 6424576
• 负责人: NICOLA J MASON
• 金额: $ 12.63万
• 依托单位: UNIVERSITY OF PENNSYLVANIA
• 依托单位国家: 美国
• 财政年份: 2002
• 资助国家: 美国
• 起止时间: 2002-09-01 至 2005-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6424576
• 关键词: T lymphocyte; Toxoplasma gondii; bone marrow transplantation; cell migration; cellular immunity; cytokine receptors; dendritic cells; flow cytometry; genetic susceptibility; immunocytochemistry; immunogenetics; immunomagnetic separation; immunoregulation; interferon gamma; interleukin 12; laboratory mouse; microorganism immunology; natural killer cells; nuclear factor kappa beta; protein biosynthesis; receptor expression; tissue /cell culture

DESCRIPTION (provided by applicant): The overall aim of this proposal is to understand the role of c-Rel, a member of the NF-kappaB family of transcription factors in regulation of the immune response to the opportunistic pathogen, Toxoplasma gondii. Athough the NF-kappaB family members are associated with the regulation of immune function required for innate and adaptive immunity, little is known about their actual role during infection. Patients with primary and acquired immune deficiencies are highly susceptible to T. gondii infection. Resistance to this pathogen is dependent upon the ability of IL-12 to stimulate the production of IFN-gamma. c-Rel is associated with many events leading to the production of IFN-gamma. For example, c-Rel is associated with the production of IL-12 and is involved in the intracellular signaling pathways of many immune molecules such as CD28 and TNF alpha that enhance IFN-gamma production by NK cells and T cells. Furthermore, c-Rel binding sites have been identified in the promoter of the IL-2 gene and c-Rel -/- T cells are deficient in the production of IL-2 and exhibit proliferation defects. Our studies have shown that c-Rel -/- mice have an increased susceptibility to T. gondii associated with increased numbers of parasites and reduced IFN-gamma production. Preliminary studies suggest that there is an early defect in the production of IL-12 at the site of infection. We have also shown in vivo and in vitro, that c-Rel is essential for IL-12 production from macrophages but not dendritic cells. Based on these preliminary studies, we propose to perform experiments which address the role of c-Rel in the production of IL-12 and IFN-gamma. These studies will allow us to further understand the mechanisms responsible for the increased susceptibility of c-Rel -/- mice to T gondii. In addition, IL-12 and IFN-gamma mediate resistance to many intracellular viral, bacterial and parasitic infections. Our studies will allow us to further understand the mechanisms responsible for the production of IFN-gamma, a cytokine that is critical for resistance to many of the opportunistic infections which affect patients with AIDS.

描述(由申请人提供)：本提案的总体目标是 了解转录因子-kappaB家族成员c-rel的作用 调节对机会性病原体的免疫反应的因素， 弓形虫。尽管核因子-kappaB家族成员与 调节先天免疫和获得性免疫所需的免疫功能， 人们对它们在感染过程中的实际作用知之甚少。患有疾病的患者 原发和获得性免疫缺陷对弓形虫高度敏感 感染。对这种病原体的抵抗力取决于IL-12的能力 刺激干扰素-γ的产生。C-Rel与许多事件相关 导致干扰素-γ的产生。例如，c-rel与 IL-12的产生并参与细胞内信号转导 许多免疫分子如CD28和肿瘤坏死因子α增强的途径 NK细胞和T细胞产生干扰素-γ。此外，c-rel结合位点 已在IL-2基因启动子和c-Rel-/-T细胞中发现 缺乏IL-2的产生，并表现出增殖缺陷。我们的 研究表明，c-rel-/-小鼠对T。 与寄生虫数量增加和干扰素-γ降低相关的弓形虫 制作。初步研究表明，儿童的大脑存在早期缺陷。 感染部位产生IL-12。我们还在活体内展示了 在体外，c-Rel对于巨噬细胞产生IL-12是必不可少的，但 而不是树突状细胞。在这些初步研究的基础上，我们建议 关于c-rel在IL-12和IL-12的产生中的作用的实验 干扰素-γ。这些研究将使我们能够进一步了解这些机制。 导致c-rel-/-小鼠对弓形虫的易感性增加。在……里面 此外，IL-12和干扰素-γ介导了对许多细胞内病毒的耐药性， 细菌和寄生虫感染。我们的研究将使我们能够进一步 了解干扰素-γ产生的机制，a 对抵抗许多机会主义者至关重要的细胞因子 影响艾滋病患者的感染。