Regulation of Innate Immunity by Virulence Factors

毒力因子对先天免疫的调节

• 批准号: 6958609
• 负责人: Alejandro Aballay
• 金额: $ 22.48万
• 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/6958609
• 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）：该探索性建议的目的是解决秀丽隐杆线虫是否可以使用的问题来提供对细菌毒力因子调节宿主基因表达以抑制整个动物水平上的先天免疫的理解的理解的见解。许多细菌病原体，包括生物战的潜在药物，共享感染和殖民多种动物的策略。这表明毒力因子与宿主中其靶标之间的相互作用是一个古老的起源，并打开了使用替代性的非魔力模型来加速可用于干预的病原体和宿主信号通路的鉴定和表征。我们一直在使用一种遗传学方法来研究细菌毒力因子及其靶标之间的相互作用。使用正向和反向遗传学方法，我们已经确定了秀丽隐杆线虫和哺乳动物中发病机理所需的各种沙门氏菌毒力相关的基因，包括与型III型沙门氏菌分泌系统（TTSS）相关的基因，该基因专用于导出效应蛋白，这些蛋白可以通过与宿主细胞细胞的特定干扰来促进细菌病原体。我们已经表明，在秀丽隐杆线虫肠细胞中表达时，效应蛋白SPTP通过靶向p38 mark信号通路，使动物更容易受到肠链球菌的影响，这对于哺乳动物的先天免疫也很重要。该提案的具体目的是：1）使用微阵列进行转录分析分析，以确定特定的先天免疫基因，这些基因受肠链球菌毒力因子的肠道表达调节。 2）使用秀丽隐杆线虫RNAi文库鉴定灭活后增强或抑制通过在秀丽隐杆线虫中毒力因子表达施加的对肠链球菌表型的敏感性增加的基因。 3）阐明目标1和2中鉴定的基因促成秀丽隐杆线虫先天免疫途径的机制。