Regulation of Innate Immunity by Virulence Factors

毒力因子对先天免疫的调节

• 批准号: 7090098
• 负责人: Alejandro Aballay
• 金额: $ 18.8万
• 依托单位: DUKE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2005
• 资助国家: 美国
• 起止时间: 2005-07-15 至 2007-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7090098
• 关键词: Caenorhabditis elegans; RNA interference; Salmonella; biological signal transduction; gene expression; genetic susceptibility; immune response; immunity; immunoregulation; microarray technology; mitogen activated protein kinase; phenotype; technology /technique development; virulence

DESCRIPTION (provided by applicant): The goal of this exploratory proposal is to address the question of whether C. elegans can be used to provide insights into the understanding of the mechanisms by which bacterial virulence factors regulate host gene expression to inhibit innate immunity at the whole animal level. Many bacterial pathogens, including potential agents of biological warfare, share strategies to infect and colonize a wide range of animals. This suggests an ancient origin for the interactions between virulence factors and their targets in the host, and opens the possibility of using alternative non-vertebrate models to accelerate the identification and characterization of both pathogen and host signaling pathways that can be targeted for intervention. We have been using a genetic approach to study the interaction between bacterial virulence factors and their targets in the model genetic organism Caenorhabditis elegans. Using forward and reverse genetic approaches, we have identified a variety of Salmonella virulence-related genes required for pathogenesis in C. elegans and mammals, including genes related to the Salmonella type III secretion system (TTSS) dedicated to export effector proteins that facilitate bacterial pathogenesis by specifically interfering with host cellular processes. We have shown that when expressed in the C. elegans intestinal cells, effector protein SptP makes the animals more susceptible to S. enterica by targeting a p38 MARK signaling pathway that is also important for innate immunity in mammals. The Specific Aims of this proposal are: 1) Use microarrays to carry out transcriptional profiling analysis to identify specific innate immunity genes that are regulated by the intestinal expression of S. enterica virulence factors. 2) Use C. elegans RNAi libraries to identify genes which when inactivated enhance or suppress the increased susceptibility to S. enterica phenotype imposed by the expression of virulence factors in C. elegans. 3) Elucidate the mechanism by which the genes identified in Aims 1 and 2 contribute to C. elegans innate immunity pathways conserved in mammals.

描述（由申请人提供）：该探索性提案的目标是解决秀丽隐杆线虫是否可用于深入了解细菌毒力因子调节宿主基因表达以抑制整个动物水平的先天免疫的机制。许多细菌病原体，包括潜在的生物战剂，都采用相同的策略来感染和定植多种动物。这表明毒力因子与其在宿主中的靶标之间相互作用的古老起源，并开启了使用替代非脊椎动物模型加速识别和表征可作为干预目标的病原体和宿主信号通路的可能性。我们一直在使用遗传学方法来研究模型遗传生物秀丽隐杆线虫中细菌毒力因子与其靶标之间的相互作用。使用正向和反向遗传方法，我们鉴定了秀丽隐杆线虫和哺乳动物发病所需的多种沙门氏菌毒力相关基因，包括与沙门氏菌 III 型分泌系统 (TTSS) 相关的基因，该系统致力于输出效应蛋白，通过特异性干扰宿主细胞过程来促进细菌发病。我们已经证明，当在线虫肠道细胞中表达时，效应蛋白 SptP 通过靶向 p38 MARK 信号通路使动物更容易受到肠沙门氏菌的影响，而 p38 MARK 信号通路对哺乳动物的先天免疫也很重要。该提案的具体目标是：1）利用微阵列进行转录谱分析，以确定受肠沙门氏菌毒力因子肠道表达调节的特定先天免疫基因。 2) 使用秀丽隐杆线虫RNAi文库来鉴定基因，当失活时，这些基因会增强或抑制由于秀丽隐杆线虫中毒力因子的表达而引起的对肠沙门氏菌表型的易感性增加。 3) 阐明目标 1 和 2 中鉴定的基因对哺乳动物中保守的线虫先天免疫途径做出贡献的机制。