The Role of NKG2D/DAP10 in Toxoplasma gondii Infection

描述（由申请人提供）：食物和水媒原生动物感染是全球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。弓形虫是一种B类优先病原体，具有良好的小动物模型，并且易于进行遗传操作。口腔感染T.易感小鼠品系中的弓形虫导致炎症和回肠炎。在评估T.我们已经鉴定出信号衔接蛋白DAP 10在保护小鼠免受致死性感染、弓形虫复制和回肠炎中的重要性。DAP 10是活化免疫受体NKG 2D的信号适配器，其识别应激、感染和转化细胞上的配体。DAP 10缺陷小鼠在NK细胞上表达NKG 2D，但在CD 8 + T细胞或γ/δ-T细胞上不表达。这些小鼠对T.刚地。DAP 10-/-小鼠有更严重的肠道炎症和坏死，脾脏中寄生虫负荷更高，并且在T.野生型小鼠通常存活的弓形虫。本提案中概述的研究旨在确定DAP 10-/-小鼠的易感性增加是否是由于T.由于缺乏表达DAP 10的CD 8 + T细胞、巨噬细胞和树突状细胞的免疫应答，或由于继发于肠中NKG 2D/DAP 10介导的CD 8 + T细胞调节功能丧失的肠坏死，导致肠中弓形虫感染。我们还将直接检验DAP 10-/-小鼠中易感性增加是由于缺乏NKG 2D信号传导的假设。这些研究将进一步阐明口服T.弓形虫，并提供了重要的见解，顶复门免疫学以及粘膜免疫口腔病原体。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，并且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免疫受体NKG 2D，对病原体的天然先天免疫应答至关重要。这项研究的目的是确定其在口腔感染T。刚地。

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.