Interferon gamma Dependent Innate Immunity to Cryptosporidium parvum

对微小隐孢子虫的干扰素γ依赖性先天免疫

• 批准号: 7152352
• 负责人: BRETT A LEAV
• 金额: $ 16.3万
• 依托单位: TUFTS MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2006
• 资助国家: 美国
• 起止时间: 2006-04-01 至 2008-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7152352
• 关键词: Cryptosporidium; antigens; human; immune response; immunity; infection; interferon gamma; lymphocyte

DESCRIPTION (provided by applicant): Cryptosporidium sp. (Cp) are enteric protozoan parasites that cause significant morbidity and mortality particularly in immunocompromised individuals for whom there is no effective therapy. Our understanding of the immune response to the parasite, particularly with respect to the earliest events by which the parasite is recognized by the host, is incomplete. The overall goal of this project is to understand the mechanism by which the host mucosal immune system initially recognizes and is activated to control Cp. Our preliminary studies have demonstrated the rapid activation of intestinal intraepithelial lymphocytes in response to Cp infection. Our hypothesis is that mucosal lymphocytes of the intestine are necessary for the resistance to and control of Cp in mice through an innate IFNy dependent mechanism. The specific aims are to: 1) directly demonstrate that mucosal lymphocytes of the intestine are a source of IFNy in mice acutely infected with Cp and 2) that these cells are necessary for innate resistance and control of infection and to determine if the activation of these cells occurs through an antigen independent mechanism. In the first specific aim we will use a transgenic IFNy reporter mouse to demonstrate the early cellular sources of IFNy. In the second aim we will perform adoptive transfer of these cells into IFNy -/- mice prior to challenge with Cp to show that these cells are protective and we will determine if this immune response is antigen independent. This will be accomplished by assessing the resistance of susceptible IFNy -/- mice to Cp infection after the adoptive transfer of CDS T cells specific for ovalbumin (OT-I mice). In summary, this application will focus on the role of mucosal lymphocytes in the primary IFNy dependent immune response in mice to Cp. Better understanding of this innate immune response to Cp, may ultimately lead to the discovery of either pathogen-derived molecules with potent adjuvant properties or host-derived pathogen recognition molecules that could be used in the development of vaccines to enhance the immunity of animals and humans.

描述（由申请方提供）：隐孢子虫属（Cp）是肠道原生动物寄生虫，可导致显著的发病率和死亡率，特别是在免疫功能低下的个体中，对这些个体没有有效的治疗方法。我们对寄生虫的免疫反应的理解，特别是关于寄生虫被宿主识别的最早期事件，是不完整的。该项目的总体目标是了解宿主粘膜免疫系统最初识别并激活以控制Cp的机制。我们的初步研究表明，快速激活肠上皮内淋巴细胞在响应Cp感染。我们的假设是肠的粘膜淋巴细胞通过先天IFN γ依赖性机制对于小鼠中Cp的抗性和控制是必需的。具体目标是：1）直接证明肠的粘膜淋巴细胞是急性感染Cp的小鼠中IFN γ的来源，和2）这些细胞对于先天抗性和感染控制是必需的，并确定这些细胞的活化是否通过抗原非依赖性机制发生。在第一个具体目标中，我们将使用转基因IFN γ报告小鼠来证明IFN γ的早期细胞来源。在第二个目的中，我们将在用Cp攻击之前将这些细胞过继转移到IFN γ-/-小鼠中，以显示这些细胞是保护性的，并且我们将确定这种免疫应答是否是抗原非依赖性的。这将通过在过继转移对卵清蛋白特异性的CD 8 T细胞（OT-I小鼠）后评估易感IFN γ-/-小鼠对Cp感染的抗性来实现。总之，本申请将集中于粘膜淋巴细胞在小鼠对Cp的初级IFN γ依赖性免疫应答中的作用。更好地理解这种对Cp的先天免疫应答，可能最终导致发现具有有效佐剂特性的病原体衍生分子或宿主衍生的病原体识别分子，这些分子可用于开发疫苗以增强动物和人类的免疫力。