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: 7229801
• 负责人: WARD D. HONORINE
• 金额: $ 27.7万
• 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 2009-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7229801
• 关键词: Adjuvant; Adoptive Cell Transfers; Adoptive Transfer; Affect; Animals; Antigens; C57BL/6 Mouse; CD4 Positive T Lymphocytes; CD8B1 gene; Categories; Cells; Centers for Disease Control and Prevention (U.S.); Cryptosporidiosis; Cryptosporidium; Cryptosporidium parvum; Distal part of ileum; Enteral; Event; Future; Goals; Hour; Human; Immune; Immune response; Immune system; Immunity; Immunocompromised Host; Individual; Infection; Infection Control; Interferon Type II; Interferons; Intestinal Mucosa; Intestines; Lead; Light; Lymphocyte; Modeling; Morbidity - disease rate; Mus; National Institute of Allergy and Infectious Disease; Natural Immunity; Natural Killer Cells; Ovalbumin; Parasites; Population; Production; Property; Reporter; Research Design; Research Personnel; Resistance; Risk; Role; Source; T-Lymphocyte; Testing; Transgenic Organisms; United States Food and Drug Administration; Water Supply; Work; biodefense; congenic; cytokine; in vivo; intraepithelial; mortality; mouse model; novel; pathogen; programs; receptor; response; vaccine development

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（由申请人提供）：隐孢子虫sp. （Cp）是肠道原生动物寄生虫，可引起显著的发病率和死亡率，特别是在没有有效治疗的免疫功能低下个体中。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事件，是不完整的。本项目的总体目标是了解宿主粘膜免疫系统最初识别和激活以控制Cp的机制。我们的初步研究已经证明肠上皮内淋巴细胞在Cp感染反应中快速激活。我们的假设是肠道粘膜淋巴细胞通过先天的IFNy依赖机制对小鼠对Cp的抵抗和控制是必要的。具体目的是：1)直接证明肠粘膜淋巴细胞是急性感染Cp小鼠中IFNy的来源；2)这些细胞是先天抵抗和感染控制所必需的，并确定这些细胞的激活是否通过抗原独立机制发生。在第一个特定目标中，我们将使用转基因IFNy报告小鼠来证明IFNy的早期细胞来源。在第二个目标中，我们将在用Cp攻击之前将这些细胞过继转移到IFNy -/-小鼠体内，以证明这些细胞具有保护作用，我们将确定这种免疫反应是否与抗原无关。这将通过评估易感IFNy -/-小鼠在过继转移卵白蛋白特异性CDS T细胞（OT-I小鼠）后对Cp感染的抵抗力来完成。总之，本研究将重点关注粘膜淋巴细胞在小鼠对Cp的原发性IFNy依赖免疫应答中的作用。更好地了解这种对Cp的先天免疫应答，可能最终导致发现具有强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。