Innate immunity and dendritic cells in cryptosporidiosis

隐孢子虫病中的先天免疫和树突状细胞

基本信息

批准号：
7272680
负责人：
SAUL r TZIPORI
金额：
$ 41.28万
依托单位：
TUFTS UNIVERSITY BOSTON
依托单位国家：
美国
项目类别：
财政年份：
2006
资助国家：
美国
起止时间：
2006-08-15 至 2011-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7272680
关键词：
Acute Address Age Bone Marrow Categories Cell Line Cells Chronic Cryptosporidiosis Cryptosporidium Cryptosporidium parvum Data Dendritic Cells Dendritic cell activation Development Diarrhea Drug Formulations Elements Enteral Epithelial Cells Event Exposure to Future Gastroenteritis Gene Expression Genetic Goals Human Immune Immune response Immune system Immunity Infection Interleukin-12 Intervention Intestines Invaded Knockout Mice Knowledge Laboratories Lead Life Ligands Link Matched Group Measures Microarray Analysis Morbidity - disease rate Mus Natural Immunity Nature Pan Genus Parasites Phenotype Play Prevention Prevention therapy Production Propionibacterium acnes Proteins Protozoa Receptor Signaling Recombinants Recovery Reporting Research Personnel Resistance Resistance Process Role Spleen Surface System TNFRSF5 gene Techniques Testing Therapeutic Corynebacterium Parvum Toll-like receptors Up-Regulation Vaccine Adjuvant Vaccine Design base cytokine design human disease innovation monocyte mortality parasite invasion pathogen programs research study response ward wasting

项目摘要

DESCRIPTION (provided by applicant): This application is in response to RFA-AI-05-042 on Innate Immunity to Category B protozoa of which Cryptosporidium spp rank among the most significant. Two species, C. hominis and C. parvum, are linked with human cryptosporidiosis, a serious cause of morbidity and mortality worldwide, and against which there is no effective therapy of prevention. Our goal is to elucidate the mechanisms by which immune cells initiate resistance against cryptosporidiosis with a view that a better understanding of the various components of the immune response will lead to development of effective vaccines and adjuvants to combat the infection in humans. Our central hypothesis is that dendritic cells recognize Cryptosporidium through Toll like receptor(s) which initiate the process of resistance against parasite invasion. We base this on the observations that: 1) dendritic cells sense pathogens through Toll-like receptors which lead to the initiation of adoptive immune responses, 2) proinflammatory cytokine IL-12, predominately produced by dendritic cells, is critical in controlling Cryptosporidium infection, and 3) bone marrow-derived CD40-positive cells are required for mice to clear C. parvum infection. Based on these observations, the specific aims are designed to investigate the innate immune response to cryptosporidiosis with a view to determining the mechanisms of Toll-like receptor signaling that lead to such responses, using both mice and human dendritic cells. The specific aims are to: 1) characterize the role of mouse dendritic cells in the innate immune response against C. parvum infection; 2) determine the nature of activation of human dendritic cells upon infection with C. parvum or C. hominis; 3) identify the Toll-like receptor used by Cryptosporidium and isolate TLR activating ligand(s) expressed by the parasite. The proposed studies will provide the basis for understanding the mechanisms of innate immune recognition and response to parasite invasion necessary for future design of vaccines and other methods of interventions.

描述（由申请人提供）：本申请是对关于 B 类原生动物先天免疫的 RFA-AI-05-042 的回应，其中隐孢子虫属于最重要的。人隐孢子虫和小隐孢子虫这两个物种与人类隐孢子虫病有关，隐孢子虫病是全世界发病和死亡的严重原因，目前尚无有效的预防疗法。我们的目标是阐明免疫细胞启动对隐孢子虫病的抵抗力的机制以便更好地了解免疫反应的各个组成部分，从而开发出有效的疫苗和佐剂来对抗人类感染。我们的中心假设是树突状细胞通过 Toll 样受体识别隐孢子虫，从而启动抵抗寄生虫入侵的过程。我们基于以下观察：1) 树突状细胞通过 Toll 样受体感知病原体，从而引发过继性免疫反应，2) 主要由树突状细胞产生的促炎细胞因子 IL-12 对于控制隐孢子虫感染至关重要， 3) 小鼠需要骨髓来源的 CD40 阳性细胞来清除微小念珠菌感染。基于这些观察，具体目标是利用小鼠和人类树突状细胞研究对隐孢子虫病的先天免疫反应，以确定导致此类反应的 Toll 样受体信号传导机制。具体目标是：1）表征小鼠树突状细胞在先天性针对微小念珠菌感染的免疫反应； 2)确定人树突状细胞在感染微小念珠菌或人念珠菌后激活的性质； 3) 鉴定隐孢子虫使用的 Toll 样受体并分离寄生虫表达的 TLR 激活配体。拟议的研究将为了解先天免疫识别和对寄生虫入侵的反应机制提供基础，这对于未来疫苗和其他干预方法的设计是必需的。