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; 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）：食物和水传播的原生动物感染是全世界严重人类疾病的常见原因。 Apicomplexa由许多引起疾病的原生动物组成，包括疟原虫，弓形虫，隐孢子虫和巴贝西亚。 Toxoplasma Gondii是B类优先病原体，具有出色的小动物模型，并且可以适合基因操纵。在易感小鼠菌株中用T. gondii的口腔感染导致炎症和回肠炎。在评估对T. gondii的先天免疫力的研究中，我们已经确定了信号转络蛋白DAP10，对于保护小鼠免受致命感染，毒质量复制和卵巢炎而言很重要。 DAP10是激活免疫感受器NKG2D的信号转移，它识别压力，感染和转化的细胞上的配体。缺乏DAP10的小鼠在NK细胞上表达NKG2D，但在CD8+ T细胞或γ/Delta-T细胞上不表达NKG2D。这些小鼠更容易受到T. gondii的口服挑战。 DAP10 - / - 小鼠具有更严重的肠炎和坏死，脾脏的寄生虫负担更高，并以野生型小鼠的常规生存而屈服于感染。该提案中概述的研究旨在确定DAP10 - / - 小鼠的敏感性增加是否是由于肠道t. gondii在肠道中的复制增加，这是由于表达CD8+ T细胞，巨噬细胞和树突状细胞的DAP10缺乏免疫反应，或者由于小肠而导致neCrisis的损失，导致nkg2d/dapsy ins in ked+ the+ the+ the+ the+ the+ the。我们还将直接检验以下假设：DAP10 - / - 小鼠的敏感性增加是由于缺乏NKG2D信号传导所致。这些研究将进一步描绘出对T. gondii口服挑战的先天免疫反应，并为Apicomplexan免疫学以及对口腔病原体的粘膜免疫提供重要见解。与公共卫生相关的是：弓形虫弓形虫是一种常见且重要的人类病原体，是包括疟疾在内的其他原生动物病原体的模型。我们已经确定了激活的免疫受体NKG2D对于天然对病原体的先天免疫反应很重要。这项赠款的研究旨在定义其在T. gondii的口腔感染中的作用。