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（申请人提供） 摘要：结核病的全球流行尚未减弱。一个特别危险的临床菌株家族是“ W-Beijing”家族，其中许多家族具有高度耐药性[MDR]。这些菌株在世界范围内的大量和相对较快的传播使人们相信这些特定的分离株具有抵抗甚至颠覆宿主免疫反应的能力或财产。申请人研究小组中的创新工作发现了至少其中一些分离株可以诱导FOXP3+调节性T细胞，从而干扰小鼠保护性免疫的适当表达。此外，在高度相关的豚鼠模型中，申请人发表了新的流式细胞术技术，以[第一次]允许宿主肺免疫反应的定义。在第二个模型中，许多这样的W-北京菌株引起了极严重的肺病理学，远比使用结核分枝杆菌的“实验室菌株”的肺部病理差得多。这是一个非常重要的一点，因为迄今为止，所有新的疫苗候选者都仅针对这些实验室菌株进行了测试。在此提案中，我们将使用创新的新转基因小鼠模型来解决新鉴定的T细胞子集在调节或颠覆这种非常严重的病原体的宿主免疫中的作用，并使用我们的III级生物安全设施。此外，我们将继续开发创新的新方法，将这些研究应用于[当前试剂限制]豚鼠模型。这些研究将包括三种w-beijing菌株，这些菌株引起肺病理范围[中度至极端]病理[以及我们向NIH提交一项建议，以使这三个进行完全基因组测序]，并有几个表征的药物敏感/耐药性/耐药性遗传对匹配的概念，以测试对耐药性的概念的概念。 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文件最近强调的那样，几乎没有关于宿主对这种疾病的MDR菌株迅速传播流行的宿主反应和基本生物学的了解，以及它们对这些机制的潜在颠覆。此类信息对于理性疫苗设计至关重要。