Mouse models for TB infection across the lifespan

整个生命周期的结核感染小鼠模型

• 批准号: 8772193
• 负责人: Nancy R Manley
• 金额: $ 22.35万
• 依托单位: UNIVERSITY OF GEORGIA
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-06-02 至 2016-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8772193
• 关键词: Acute; Affect; Age; Aging; Alleles; Animal Model; Biological Assay; Cell Differentiation process; Cells; Cessation of life; Characteristics; Disease; Disease Progression; Elderly; Environment; Goals; Human; Immune; Immune System Diseases; Immune response; Immune system; Immunology; In Vitro; Individual; Infection; Inflammatory; Life Expectancy; Longevity; Masks; Mediator of activation protein; Memory; Modeling; Morbidity - disease rate; Mouse Strains; Mus; Mutation; Mycobacterium tuberculosis; Neonatal; Outcome; Pathology; Peripheral; Phenotype; Physiological; Play; Population; Predisposition; Production; Regulation; Relative (related person); Reporting; Risk; Role; Severity of illness; Symptoms; T memory cell; T-Lymphocyte; Testing; Thymic epithelial cell; Thymus Gland; Time; Tuberculosis; Vaccination; Virus Diseases; Wild Type Mouse; World Health Organization; age effect; age group; age related; aged; base; effective therapy; genetic resource; immune function; immunosenescence; in vivo; insight; mortality; mouse model; novel; pathogen; premature; programs; public health relevance; reactivation from latency; response; transcription factor; treatment strategy; virtual; young adult

DESCRIPTION (provided by applicant): Mycobacterium tuberculosis (Mtb) continues to cause significant morbidity and mortality worldwide. TB in the elderly can arise directly from a new infection, reflecting the documented general increase in susceptibility of the elderly to numerous infections including Mtb, or reactivate from a previously latent Mtb infection, and is frequently attributed to deficits in adaptive immune function. However, little experimental information exists to define the specific aspects of immune dysfunction that contribute to the increased susceptibility of the elderly to Mtb infection. There are numerous changes in central immune function (thymus production of T cells), peripheral T cell repertoire and functional parameters, and in the peripheral environment (e.g. increased inflammatory conditions) with aging, any or all of which could contribute to the increased risk for active Mtb infection in the elderly. However, each of these mechanisms would be best approached therapeutically in different ways. Thus, our long-term goal is to identify the specific contributions of these immune changes to increased rates of Mtb infection in the elderly and develop effective treatment strategies. In this proposal, we will use unique mouse genetic resources developed in the Manley lab to test two hypotheses: that this innate-like TEM subpopulation plays a critical role in controlling Mtb infection and establishing latency, and that time since thymic involution plays a significant role in enhanced rates of Mtb primary infections and latency reactivation in the elderly. In Aim 1 we will determine whether innate-like TEM peripheral T cells can enhance the immune response to primary Mtb infection, using the Foxn1¿/¿ mouse model and in vitro and in vivo assays. In Aim 2 we will test whether enhanced disease progression and severity of active Mtb infection in the elderly is due to changes in the peripheral T cell pool caused by thymic involution, or by the physiological effects of aging using Foxn1Z/Z mice that undergo premature thymic involution. These studies may provide new insights into the T cell mechanisms regulating Mtb infection in the elderly, and define new mouse models that may be useful for the study of the immune response to Mtb infection.

描述（由申请人提供）：结核分枝杆菌 (Mtb) 继续在全球范围内导致老年人显着发病和死亡，结核病可能直接由新感染引起，这反映了有记录的老年人对包括 Mtb 在内的多种感染的易感性普遍增加。从先前潜伏的结核分枝杆菌感染中重新激活，通常归因于适应性免疫功能的缺陷，但是，很少有实验信息可以确定导致增加的免疫功能障碍的具体方面。随着年龄的增长，中枢免疫功能（T 细胞的胸腺生成）、外周 T 细胞库和功能参数以及外周环境（例如炎症条件增加）发生了许多变化。这可能会增加老年人活动性结核分枝杆菌感染的风险。然而，每种机制最好以不同的方式进行治疗，因此，我们的长期目标是确定这些免疫变化对增加感染率的具体贡献。的老年人 Mtb 感染并制定有效的治疗策略 在这项提案中，我们将使用 Manley 实验室开发的独特小鼠遗传资源来检验两个假设：这种先天性 TEM 亚群在感染中发挥着关键作用。 控制 Mtb 感染并建立潜伏期，而胸腺复旧后的时间在老年人 Mtb 原发感染率和潜伏期再激活中发挥着重要作用。在目标 1 中，我们将确定先天样 TEM 外周 T 细胞是否可以增强免疫反应。对于原发性 Mtb 感染，使用 Foxn1¿ /¿在目标 2 中，我们将测试老年人活动性结核分枝杆菌感染的疾病进展和严重程度是否是由于胸腺退化引起的外周 T 细胞库的变化，或者是衰老的生理效应所致。使用经历过早胸腺退化的 Foxn1Z/Z 小鼠进行的这些研究可能为调节老年人 Mtb 感染的 T 细胞机制提供新的见解，并定义可能有助于研究 Mtb 免疫反应的新小鼠模型。结核分枝杆菌感染。