IL-12 Regulation in Leishmania Infected Dendritic Cells

IL-12 在利什曼原虫感染的树突状细胞中的调节

基本信息

批准号：
7382523
负责人：
MARY A MCDOWELL
金额：
$ 24.42万
依托单位：
UNIVERSITY OF NOTRE DAME
依托单位国家：
美国
项目类别：
财政年份：
2005
资助国家：
美国
起止时间：
2005-03-15 至 2010-02-28
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7382523
关键词：
Affect Animal Model Automobile Driving Binding Cell Differentiation process Cells Class Clinical Complex Cutaneous Cytokine Network Pathway Dendritic Cells Disease Disease Outcome Environment Event Evolution Galactose Binding Lectin Genes Genetic Transcription Goals Healed Hour Human Immune Immune system Immunity In Vitro Individual Infection Inflammatory Response Interleukin-12 Interleukin-12 Gene Invaded Lead Leishmania Leishmania major Leishmaniasis Lesion Life Mediating Messenger RNA Modeling Modification Molecular Molecular Structure Mononuclear Morbidity - disease rate Parasites Pattern Phagocytes Phenotype Play Polysaccharides Post-Transcriptional Regulation Process Production Prunella vulgaris Range Recording of previous events Regulation Relative (related person)Role Signal Pathway Signal Transduction Signal Transduction Pathway Site Specificity Staging Structure Surface Surveys System Systemic disease T-Lymphocyte TNFSF5 gene Today Toll-Like Receptor 2 Vaccinated Vaccines Virulent Visceral cytokine healing interest interleukin-12 subunit p35 interleukin-12 subunit p40 macrophage microorganism mortality pathogen response vaccine development

项目摘要

DESCRIPTION (provided by applicant): Dendritic cells (DC) are among the first cells encountered by infecting pathogens; acting as sentries, these cells recognize invading microorganisms and secrete signals that dictate class differentiation of adaptive immunity. The mechanisms that mediate the ability of DC to discriminate between pathogens remain elusive. Using experimental Leishmania infection we will evaluate the precise contributions that host and parasite factors play in generating interleukin-12 (IL-12), the critical cytokine driving Thl cell differentiation. To model the initial events during Leishmania infection, we employ an in vitro system of human DC and infectious stage parasites. We previously demonstrated that the induction of IL-12 by these cells is Leishmania species dependent and requires CD40L stimulation. Whereas infection by species responsible for fatal visceral disease (L. donovani) fail to induce IL-12, infection with L. major a species associated with self-limiting cutaneous disease, primes DC for IL-12 secretion. The overall goal of this proposal is to identify the molecular determinants of these disparate IL-12 responses. Specific Aim 1 will determine the point of regulation at which Leishmania spp. modulate IL-12 production. A conditional approach will be taken to determine if transcriptional or post-transcriptional regulation plays a role in the production of IL-12 in response to Leishmania infection. Specific Aim 2 will identify the Leishmania factors that regulate IL-12 induction by specifically investigating the influence of different structural modifications on the parasite surface. Intrinsic differences in the ability of Leishmania parasites to prime DC for IL-12 production likely influences the capability of these parasites to activate Thl adaptive responses. These studies are underscored by the fact that the immune mechanisms elicited by live L. major infection leads to powerful life-long immunity. Elucidation of the critical components involved will have ramifications for other pathogen infections that require sustained cell-mediated responses for protection.

描述（由申请人提供）：树突状细胞（DC）是感染病原体遇到的第一个细胞之一；这些细胞充当哨兵，识别出入侵的微生物和分泌信号，这些信号决定了适应性免疫的阶级分化。介导DC区分病原体能力的机制仍然难以捉摸。使用实验性利什曼原虫感染，我们将评估宿主和寄生虫因子在产生白介素12（IL-12）（IL-12）的确切贡献，这是关键的细胞因子驱动THL细胞分化。为了模拟利什曼原虫感染期间的初始事件，我们采用了人类DC和感染性寄生虫的体外系统。我们先前证明，这些细胞诱导IL-12是利什曼原虫物种依赖的，需要CD40L刺激。而导致致命内脏疾病（L. donovani）的物种感染未能诱导IL-12，l。与L. Major A的感染。该提案的总体目标是确定这些不同IL-12反应的分子决定因素。具体目标1将确定利什曼原虫属的监管点。调节IL-12产生。将采用有条件的方法来确定转录或转录后调节是否在响应利什曼尼亚感染的IL-12产生中起作用。具体目标2将通过专门研究不同结构修饰对寄生虫表面的影响来确定调节IL-12诱导的利什曼原虫因子。利什曼原虫寄生虫对IL-12产生的DC素的能力的内在差异可能会影响这些寄生虫激活THL自适应反应的能力。这些研究强调了以下事实：现场L.主要感染引起的免疫机制导致了强大的终身免疫力。阐明所涉及的关键成分将对需要持续的细胞介导的反应以保护的其他病原体感染产生影响。