Innate Immunity Driven Th1/Th2 bias in Leishmaniasis

利什曼病中先天免疫驱动的 Th1/Th2 偏差

• 批准号: 6802681
• 负责人: KEITH G NELSON
• 金额: $ 9.5万
• 依托单位: COLORADO STATE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2003
• 资助国家: 美国
• 起止时间: 2003-09-30 至 2006-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6802681
• 关键词: Leishmania major; complement receptor; cytokine; gene targeting; genetically modified animals; helper T lymphocyte; immunity; immunologic receptors; laboratory mouse; leishmaniasis; macrophage; pathologic process; phagocytosis; polymerase chain reaction; protozoal antigen; tissue /cell culture; toll like receptor

DESCRIPTION (provided by applicant): The immediate goal of the candidate, Keith G. Nelson, DVM, is to complete a mentored training program in research of immunopathogenesis of Leishmania infection, which will culminate in both the PhD degree and continued postdoctoral study. Dr. Nelson's long-term goal is to become a principal investigator conducting research on the immune response to, pathogenesis and prevention of leishmaniasis and other vector-borne parasitic pathogens. The research-training program will be centered on the laboratory of Dr. Richard G. Titus, in the immunoparasitology Research Group at Colorado State University. The research environment has a strong history of extramural funding and biomedical scientist training. The candidate's training plan consists of laboratory and didactic instruction in contemporary molecular and immunological techniques and research methods applied to an animal model of leishmaniasis. The proposed research utilizes an established murine model of Leishmania infection to investigate the early stages of the immune response to Leishmania major(Lm) and subsequent Type 1 T cell vs. Type 2 T cell (Th1/Th2) differentiation, with a focus on the macrophage receptors and parasite surface antigens involved in host recognition and response. Three specific aims will be addressed: 1) to identify the macrophage complement and non-complement receptors involved in recognition, phagocytosis, and response to Lm, as well as characterizing changes in the Th1/Th2 response secondary to entry via specific macrophage receptors; 2) to characterize the role of toll-like receptors TLRs) in transducing host response to Lm infection, identifying relevant receptors and determining the effect on Th1/Th2 bias; 3) to determine the effect of major parasite surface molecules lipophosphoglycan (LPG) and gp63 on host recognition, phagocytosis and Th1/Th2 response to Lm. All of these will be addressed using in vivo infection of relevant knockout mice with LPG or gp63 deficient parasites, as well as with in vitro macrophage culture, receptor blocking, infection and co-cultivation with naive Th cells to assess functional priming. Cytokine profiles will be assessed via ELISA and RTPCR to determine Th1/Th2-associated bias and TLR mRNA will be assessed via RT-PCR. The results of these studies will provide new insights into the interactions between the primary phagocytic ceils of the innate immune response and the protozoan parasite Leishmania major. We will also gain insight into the effect of the innate immune response and pathogen recognition pathway on the establishment of Th1/Th2 responses in adaptive immunity. This information may prove to be important in the development of effective treatment, control and preventative measures in leishmaniasis, as well as furthering our knowledge of the interactions between the innate and adaptive arms of the immune system.

描述（由申请人提供）：候选人的近期目标，基思G。纳尔逊，DVM，是完成指导培训计划在利什曼原虫感染的免疫发病机制的研究，这将最终在博士学位和继续博士后研究。纳尔逊博士的长期目标是成为一名主要研究员，从事利什曼病和其他媒介传播的寄生虫病原体的免疫反应、发病机制和预防研究。研究培训计划将集中在理查德G。科罗拉多州立大学免疫寄生虫学研究小组的泰特斯说。研究环境有很强的校外资助和生物医学科学家培训的历史。候选人的培训计划包括当代分子和免疫学技术的实验室和教学指导，以及应用于利什曼病动物模型的研究方法。 拟议的研究利用已建立的利什曼原虫感染小鼠模型来研究对大型利什曼原虫（Lm）的免疫应答的早期阶段以及随后的1型T细胞与2型T细胞（Th 1/Th 2）分化，重点关注参与宿主识别和应答的巨噬细胞受体和寄生虫表面抗原。本研究的目的有三：1）鉴定参与Lm识别、吞噬和应答的巨噬细胞补体和非补体受体，以及表征通过特异性巨噬细胞受体进入后继发的Th 1/Th 2应答的变化; 2）表征Toll样受体TLR在转导宿主对Lm感染的应答中的作用，鉴定相关受体并确定对Th 1/Th 2偏倚的影响; 3）确定主要寄生虫表面分子脂磷酸聚糖（LPG）和gp 63对宿主识别、吞噬和Th 1/Th 2应答Lm的影响。所有这些都将通过使用LPG或gp 63缺陷型寄生虫体内感染相关敲除小鼠以及体外巨噬细胞培养、受体阻断、感染和与幼稚Th细胞共培养来评估功能性引发来解决。将通过ELISA和RTPCR评估细胞因子谱，以确定Th 1/Th 2相关偏倚，并将通过RT-PCR评估TLR mRNA。 这些研究的结果将为先天免疫应答的初级吞噬细胞与原虫寄生虫硕大利什曼原虫之间的相互作用提供新的见解。我们还将深入了解先天免疫应答和病原体识别途径对获得性免疫中Th 1/Th 2应答建立的影响。这些信息可能被证明是重要的，在利什曼病的有效治疗，控制和预防措施的发展，以及进一步我们的知识之间的相互作用的先天和适应性的免疫系统。