Immune modulation by highly virulent clinical isolates of M.tuberculosis

高毒力结核分枝杆菌临床分离株的免疫调节

• 批准号: 7847842
• 负责人: Diane Joyce Ordway
• 金额: $ 199.85万
• 依托单位: COLORADO STATE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-09-30 至 2013-09-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7847842
• 关键词: Address; Arts; Biology; Cavia; Clinical; Disease; Drug resistance; Epidemic; Family; Genomics; Immune response; Immunity; Laboratories; Lung; Methods; Modeling; Mus; Mycobacterium tuberculosis; National Institute of Allergy and Infectious Disease; Pathology; Property; Publishing; Reagent; Research; Role; T-Lymphocyte; T-Lymphocyte Subsets; Technology; Testing; Time; Transgenes; Tuberculosis; United States National Institutes of Health; Vaccine Design; Virulence; Virulent; Work; abstracting; fitness; immunoregulation; innovation; mouse model; novel vaccines; pathogen; public health relevance; transmission process; vaccine candidate

DESCRIPTION (Provided by the applicant) Abstract: The global epidemic of tuberculosis continues unabated. A particularly dangerous family of clinical strains is the "W-Beijing" family, many of which are highly drug resistant [MDR]. The substantial and relatively rapid transmission of these strains across the world has led people to believe that these particular isolates have some capacity or property to resist, and even subvert, the host immune response. Innovative work in the applicant's research group has uncovered the possibility that at least some of these isolates can induce Foxp3+ regulatory T cells that interfere with the proper expression of protective immunity in the mouse. Moreover, in the highly relevant guinea pig model, the applicant has published new flow cytometric technology to allow [for the very first time] the definition of the host pulmonary immune response. In this second model many of these W-Beijing strains cause extremely severe lung pathology, far worse than that seen using "laboratory strains" of Mycobacterium tuberculosis. This is a very important point, because all new vaccine candidates to date have only been tested against these laboratory strains. In this proposal we will use innovative new transgene mouse models to address the role of newly identified T cell subsets in modulating or subverting host immunity to this very serious group of pathogens, using our state of the art level III biosafety facilities. In addition, we will continue to develop innovative new methods to apply these studies to the [currently reagent-limited] guinea pig model. These studies will include three W-Beijing strains that cause a range [moderate to extremely severe] lung pathology [and for which we are submitting a proposal to the NIH to have these three undergo full genomic sequencing], and several characterized examples of drugsensitive/ drug-resistant genetically matched pairs to test the concept that acquisition of drug resistance reduces bacterial fitness, and hence virulence. Public Health Relevance: Tuberculosis is one of the most important diseases in the world. As recently emphasized by an NIAID document, virtually nothing is known about the host response to, and basic biology of, the rapidly spreading epidemic of MDR strains of this disease, and their potential subversion of these mechanisms. Such information is critical to rational vaccine design.

描述（由申请人提供） 摘要：全球结核病流行趋势有增无减。一个特别危险的临床菌株家族是“W-Beijing”家族，其中许多具有高度耐药性[MDR]。这些菌株在世界范围内大量且相对快速的传播使人们相信这些特定的分离株具有一定的能力或特性来抵抗甚至破坏宿主的免疫反应。申请人研究小组的创新工作揭示了这样的可能性：这些分离株中的至少一些可以诱导Foxp3+调节性T细胞，干扰小鼠中保护性免疫的正确表达。此外，在高度相关的豚鼠模型中，申请人发布了新的流式细胞术技术，以[首次]定义宿主肺部免疫反应。在第二个模型中，许多 W-Beijing 菌株引起极其严重的肺部病理，比使用结核分枝杆菌“实验室菌株”所见的情况严重得多。这是非常重要的一点，因为迄今为止所有新的候选疫苗都只针对这些实验室毒株进行了测试。在本提案中，我们将利用我们最先进的 III 级生物安全设施，使用创新的转基因小鼠模型来解决新鉴定的 T 细胞亚群在调节或颠覆宿主对这一非常严重的病原体群体的免疫方面的作用。此外，我们将继续开发创新的新方法，将这些研究应用于[目前试剂有限的]豚鼠模型。这些研究将包括三种 W-Beijing 菌株，它们会导致一系列[中度至极严重]肺部病理学[为此，我们正在向 NIH 提交一项提案，要求对这三种菌株进行全面基因组测序]，以及几个具有药物敏感性/耐药基因匹配对来测试耐药性的获得会降低细菌适应性，从而降低毒力的概念。 公共卫生相关性：结核病是世界上最重要的疾病之一。正如 NIAID 最近的一份文件所强调的那样，对于这种疾病的 MDR 菌株迅速蔓延的流行病的宿主反应和基本生物学，以及它们对这些机制的潜在破坏，几乎一无所知。这些信息对于合理的疫苗设计至关重要。