Defining resistance and tolerance mechanisms in hyper-susceptible mice during M. tuberculosis infection

结核分枝杆菌感染期间高易感小鼠的抵抗和耐受机制的定义

• 批准号: 10092102
• 负责人: Andrew Olive
• 金额: $ 23.1万
• 依托单位: MICHIGAN STATE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-01-29 至 2022-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10092102
• 关键词: Animals; Antigen-Antibody Complex; Antimicrobial Resistance; Automobile Driving; CASP1 gene; Cells; Cessation of life; Communicable Diseases; Defect; Disease; Disease Progression; Dissection; Effectiveness; Environment; Exposure to; Genetic; Genotype; Growth; Health; Immune; Immune response; Immunity; Immunocompromised Host; Individual; Infection; Inflammation; Inflammatory; Interleukin-10; Kinetics; Knock-out; Lung; Lung diseases; Masks; Measures; Mediator of activation protein; Modeling; Mus; Mutation; Mycobacterium tuberculosis; NADP; Oxidases; Pathway interactions; Patients; Phagocytes; Population; Predisposition; Process; Production; Prognosis; Public Health; Reporting; Resistance; Role; Signal Transduction; Therapeutic; Time; Tissues; Treatment Protocols; Tuberculosis; Vaccines; burden of illness; cytokine; disorder control; experience; experimental study; fitness; granulocyte; improved; in vivo; in vivo Model; inflammatory milieu; knockout animal; macrophage; model design; mortality; novel; novel strategies; pathogen; recruit; repaired; resistance mechanism; response; targeted treatment

Project Summary Infections with Mycobacterium tuberculosis (Mtb) result in over 1.5 million deaths annually. Unfortunately, there are no effective vaccines against pulmonary disease and current treatment regimens extend to at least six months. There is an urgent need to develop new approaches to treatment, such as host-directed therapies, that shorten treatment time and improve disease prognosis. To effectively develop new host-directed therapies, we must understand how protective pathways function mechanistically and determine how they interact with other immune networks. Using targeted genetic interaction studies, we recently discovered a strong synthetic lethal interaction between the NADPH phagocyte oxidase (Phox) and Caspase1/11 (Casp1/11) during Mtb infection. Loss of either locus individually results in minimal survival defects yet combining deletions resulted in rapid disease progression within 4 weeks post-infection. These infections were characterized by increased Mtb in the lungs and dysregulated inflammatory signals including IL1a and IL10. Here the failed host response in Phox/Casp1/11 animals will be dissected. The susceptibility of Phox/Casp1/11 animals might be due to loss of resistance mechanisms that directly control pathogen replication and/or tolerance mechanisms that control overall host health during infection. We hypothesize that loss of Phox and Caspase1/11 together results in dysregulated immune defense cascades leading to both failed resistance and tolerance during Mtb infection. We have developed models that allow the effects of tolerance and resistance to be quantified. In Aim1 defects in the antimicrobial resistance of Phox/Casp1/11 animals will be measured using ex vivo and in vivo models designed to report directly on bacterial growth and fitness independently of inflammatory differences. In Aim 2 tolerance responses in Phox/Casp1/11 animals will be examined using an in vivo model that normalizes Mtb levels between animals and directly quantifies how dysregulated inflammation contributes to susceptibility. Determining the contribution of resistance and tolerance to the susceptibility of Phox/Casp1/11 animals is a critical step to define the immune networks modulated by Phox and Casp1/11 and examine their potential as host-directed therapy targets.

项目摘要 结核分枝杆菌（Mtb）感染每年导致超过150万人死亡。不幸的是， 目前还没有有效的针对肺病的疫苗， 六个月迫切需要开发新的治疗方法，例如宿主导向疗法， 从而缩短治疗时间并改善疾病预后。为了有效地开发新的主机导向 因此，我们必须了解保护性途径如何在机制上发挥作用，并确定它们是如何发挥作用的。 与其他免疫网络相互作用。通过有针对性的遗传相互作用研究，我们最近发现了一种 NADPH吞噬细胞氧化酶（Phox）和Caspase 1/11之间的强合成致死相互作用 （Casp1/11）。任何一个基因座的缺失都会导致最小的生存缺陷， 合并缺失导致感染后4周内疾病快速进展。这些感染 其特征在于肺中Mtb增加和包括IL 1a和IL 10的炎症信号失调。 在此，将分析Phox/Casp 1/11动物中失败的宿主应答。的易感性 Phox/Casp 1/11动物可能是由于失去了直接控制病原体复制的抗性机制 和/或在感染期间控制总体宿主健康的耐受机制。我们假设失去火卫一 和Caspase 1/11共同导致免疫防御级联反应失调， 和耐药性。我们已经建立了模型，允许耐受性的影响， 阻力要量化。在Aim 1中，Phox/Casp 1/11动物的抗菌素耐药性缺陷将被 使用设计用于直接报告细菌生长和适应性的离体和体内模型测量 独立于炎症差异。在目标2中，Phox/Casp 1/11动物的耐受性反应将是 使用体内模型进行检查，该模型使动物之间的Mtb水平正常化，并直接量化 失调的炎症导致易感性。确定阻力的贡献， 对Phox/Casp 1/11动物易感性的耐受性是定义免疫网络的关键步骤 受Phox和Casp 1/11调节，并检查其作为宿主导向治疗靶点的潜力。