Role of CCL2/MCP-1 in mucosal immunity to Toxoplasma

CCL2/MCP-1在弓形虫粘膜免疫中的作用

• 批准号: 7282869
• 负责人: ERIC Y DENKERS
• 金额: $ 19.19万
• 依托单位: CORNELL UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2007
• 资助国家: 美国
• 起止时间: 2007-08-01 至 2009-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7282869
• 关键词: Role; CCL2; MCP; mucosal; immunity

DESCRIPTION (provided by applicant): Toxoplasma gondii is a major AIDS-associated pathogen that can cause severe disease or death in congenitally infected infants. The parasite is also classified as an NIAID Category B priority microorganism. The long-term objective of this application is to understand the cellular immune response mechanisms that are necessary to control infection with this opportunistic protozoan pathogen, and to determine how dysfunctional responses can lead to immunopathology and inability to control infection. Preliminary data indicate that mice lacking expression of chemokine MCP-1 (CCL2) are highly susceptible to intraperitoneal infection with T. gondii, and this is associated with defective recruitment into the peritoneal cavity of a monocyte/dendritic cell- like population co-expressing Gr-1 and MHC class II and costimulatory molecules CD80/CD86 and CD40. Other recent studies have described similar cells, although whether they mediate protection or increase susceptibility is not clear and may depend upon the infection model. The goal of the present proposal is to determine whether cells double-positive for MHC class II and Gr-1 (MHC2+Gr-1+) are recruited during the mucosal immune response to oral infection with Toxoplasma. The specific aims we will employ to address this issue are as follows. 1, Determine the effects of CCL2 deficiency during oral infection compared to intraperitoneal infection, in particular whether the chemokine mediates resistance or susceptibility to Toxoplasma, and whether lack of CCL2 alters the Th1/Th2 balance during infection. 2, Determine if CCL2 recruits MHC2+GR-1+ cells during the mucosal immune response to infection. The ability of these cells to serve as an infection reservoir and to express microbicidal molecules and cytokines (in particular, IL-12) will also be examined. These aims will be achieved by ex vivo and in vitro analyses of cells isolated from intestinal mucosal tissues. Direct visualization of MHC class II-positive and Gr-1-positive cells in intestinal mucosa of wild-type and CCL2 negative mice will be accomplished by fluorescence immunohistochemistry. These studies can be expected to deepen our understanding of how immunity to Toxoplasma is initiated in mucosal tissues and will clarify the role of MHC2+Gr-1+ cells in this process. Understanding how immunity is triggered will ultimately lead to more effective means of controlling infection with Toxoplasma and other orally transmitted AIDS-associated microbial pathogens. The relevance of the project to public health is that Toxoplasma infects between 30-80% of the human population worldwide. While normally an asymptomatic infection, with suboptimal immune function the parasite emerges as a devastating and sometimes lethal infection. This project will enhance our understanding of immunity to the parasite, leading to improved treatment strategies.

描述（由申请人提供）：弓形虫弓形虫是与艾滋病相关的主要病原体，可导致先天感染的婴儿严重疾病或死亡。该寄生虫还被归类为B类优先微生物。该应用的长期目的是了解通过这种机会性原生动物病原体控制感染所必需的细胞免疫反应机制，并确定功能障碍反应如何导致免疫病理学和无法控制感染。 Preliminary data indicate that mice lacking expression of chemokine MCP-1 (CCL2) are highly susceptible to intraperitoneal infection with T. gondii, and this is associated with defective recruitment into the peritoneal cavity of a monocyte/dendritic cell- like population co-expressing Gr-1 and MHC class II and costimulatory molecules CD80/CD86 and CD40.其他最近的研究描述了类似的细胞，尽管它们是否介导保护或增加易感性尚不清楚，并且可能取决于感染模型。本建议的目的是确定在粘膜免疫反应对口服毒素感染的粘膜免疫反应期间，是否募集了MHC II和GR-1（MHC2+GR-1+）双阳性的细胞。我们将采用的具体目的解决此问题如下。 1，确定与腹膜内感染相比，确定口腔感染期间CCL2缺乏症的作用，特别是趋化因子是否介导了抗毒素的耐药性或易感性，以及缺乏CCL2是否会在感染过程中改变TH1/TH2的平衡。 2，确定在粘膜免疫反应感染期间，CCL2是否募集了MHC2+ GR-1+细胞。这些细胞作为感染储层的能力以及表达微生物分子和细胞因子（尤其是IL-12）的能力也将进行检查。这些目标将通过离体和从肠粘膜组织分离的细胞进行体外分析来实现。野生型和CCL2负小鼠的肠粘膜中MHC II类阳性和GR-1阳性细胞的直接可视化将通过荧光免疫组织化学来实现。可以期望这些研究加深我们对粘膜组织中如何启动对弓形虫的免疫力的理解，并将阐明MHC2+ GR-1+细胞在此过程中的作用。了解如何触发免疫力最终会导致更有效的手段控制弓形虫和其他口服艾滋病相关的微生物病原体感染。该项目与公共卫生的相关性是，弓形虫在全球30-80％之间感染了人口的30-80％。虽然通常是无症状的感染，但具有次优的免疫功能，寄生虫作为毁灭性的，有时是致命的感染出现。该项目将增强我们对寄生虫免疫力的理解，从而改善治疗策略。