The Role of NKG2D/DAP10 in Toxoplasma gondii Infection

NKG2D/DAP10在弓形虫感染中的作用

• 批准号: 7756606
• 负责人: Rachel Margaret Presti
• 金额: $ 11.52万
• 依托单位: WASHINGTON UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2008
• 资助国家: 美国
• 起止时间: 2008-02-01 至 2012-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7756606
• 关键词: Adaptor Signaling Protein; Animal Model; Animals; Apicomplexa; Babesia; Bioterrorism; CD8B1 gene; Categories; Cell Line; Cells; Cessation of life; Cryptosporidium; Cyst; Data; Dendritic Cells; Disease; Disease Outbreaks; Dose; Environment; Epithelial Cells; Felis catus; Food; Food Supply; Genetic; Grant; Hematopoietic; Human; Ileitis; Immune response; Immunity; Immunohistochemistry; Immunologic Receptors; Immunology; In Vitro; Infection; Inflammation; Inflammatory; Inflammatory Bowel Diseases; Inflammatory Response; Inflammatory disease of the intestine; Ingestion; Interleukin-10; Interleukin-12; Intestinal Diseases; Intestines; Kinetics; Lead; Libraries; Ligands; Lymphocyte; Malaria; Measures; Meat; Mediating; Messenger RNA; Modeling; Mouse Strains; Mucosal Immunity; Mus; Natural Immunity; Natural Killer Cells; Nature; Necrosis; Oocysts; Oral; Parasites; Parasitic infection; Plasmodium; Predisposition; Production; Protozoa; Protozoan Infections; Public Health; Recruitment Activity; Regulation; Relative (related person); Reporter; Research Personnel; Risk; Role; Secondary to; Signal Transduction; Spleen; Stress; T-Lymphocyte; Testing; Tissues; Toxoplasma; Toxoplasma gondii; Toxoplasmosis; United States; Wild Type Mouse; Work; antimicrobial; cell transformation; cell type; cytokine; cytotoxicity; enteritis; experience; genetic manipulation; human disease; innate immune function; insight; intraepithelial; macrophage; novel; novel therapeutics; oral infection; oral pathogen; pathogen; programs; receptor; response; tool; waterborne

DESCRIPTION (provided by applicant): Food and waterborne protozoal infections are a common cause of severe human disease worldwide. The Apicomplexa consist of numerous protozoa which cause disease, including Plasmodium, Toxoplasma, Cryptosporidia, and Babesia. Toxoplasma gondii is a Category B Priority pathogen which has an excellent small animal model, and is amenable to genetic manipulation. Oral infection with T. gondii in susceptible mouse strains results in inflammation and ileitis. In studies evaluating innate immunity to T. gondii, we have identified the signaling adaptor protein, DAP10, as important in protecting mice from lethal infection, toxoplasma replication, and ileitis. DAP10 is the signaling adaptor for the activating immunoreceptor NKG2D, which recognizes ligands on stressed, infected and transformed cells. Mice deficient in DAP10 express NKG2D on NK cells, but not on CD8+ T cells or gamma/delta-T cells. These mice are more susceptible to oral challenge with T. gondii. DAP10-/- mice have more severe intestinal inflammation and necrosis, higher parasite burdens in the spleen, and succumb to infection at doses of T. gondii which wild type mice routinely survive. Studies outlined in this proposal aim to determine whether the increased susceptibility of DAP10-/- mice is due to increased replication of T. gondii in the intestine due to lack of immune response by DAP10 expressing CD8+ T cells, macrophages and dendritic cells, or due to intestinal necrosis secondary to the loss of NKG2D/DAP10 mediated regulatory function of CD8+ T cells in the intestine. We will also directly test the hypothesis that the increased susceptibility in DAP10-/- mice is due to lack of NKG2D signaling. These studies will further delineate the innate immune response to oral challenge with T. gondii, and provide important insights to apicomplexan immunology as well as mucosal immunity to oral pathogens. Relevance to public health: Toxoplasma gondii is a common and important human pathogen, and is a model for other protozoal pathogens, including malaria. We have identified the activating immune receptor, NKG2D, as important for the natural, innate immune response to pathogens. Studies in this grant aim to define its role in oral infection with T. gondii.

描述（由申请人提供）：食物和水源性原虫感染是全世界严重人类疾病的常见原因。顶复门由许多引起疾病的原生动物组成，包括疟原虫、弓形虫、隐孢子虫和巴贝虫。弓形虫是 B 类优先病原体，具有优良的小动物模型，并且适合基因操作。易感小鼠品系的弓形虫口腔感染会导致炎症和回肠炎。在评估弓形虫先天免疫的研究中，我们发现信号转导接头蛋白 DAP10 在保护小鼠免受致命感染、弓形虫复制和回肠炎方面具有重要作用。 DAP10 是激活免疫受体 NKG2D 的信号传导适配器，可识别应激、感染和转化细胞上的配体。 DAP10 缺陷的小鼠在 NK 细胞上表达 NKG2D，但在 CD8+ T 细胞或 γ/δ-T 细胞上不表达。这些小鼠更容易受到弓形虫的口服攻击。 DAP10-/-小鼠有更严重的肠道炎症和坏死，脾脏中的寄生虫负担更高，并且在弓形虫剂量下死于感染，而野生型小鼠通常可以存活。该提案中概述的研究旨在确定 DAP10-/- 小鼠的易感性增加是否是由于表达 DAP10 的 CD8+ T 细胞、巨噬细胞和树突状细胞缺乏免疫反应而导致弓形虫在肠道内的复制增加，或者是由于肠道中 NKG2D/DAP10 介导的 CD8+ T 细胞调节功能丧失继发的肠坏死。我们还将直接检验以下假设：DAP10-/- 小鼠的易感性增加是由于缺乏 NKG2D 信号传导。这些研究将进一步描述对弓形虫口腔攻击的先天免疫反应，并为顶端复合体免疫学以及针对口腔病原体的粘膜免疫提供重要见解。与公共卫生的相关性：弓形虫是一种常见且重要的人类病原体，也是包括疟疾在内的其他原虫病原体的模型。我们已经确定激活免疫受体 NKG2D 对于针对病原体的自然先天免疫反应非常重要。此项资助的研究旨在确定其在弓形虫口腔感染中的作用。