Targeting an immunomodulatory protease for adjunctive tuberculosis chemotherapy

靶向免疫调节蛋白酶用于结核病辅助化疗

基本信息

批准号：
8996134
负责人：
Jyothi Rengarajan
金额：
$ 22.76万
依托单位：
EMORY UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2015
资助国家：
美国
起止时间：
2015-02-01 至 2018-01-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8996134
关键词：
Aerosols Aftercare Antibiotic Therapy Antibiotics Antigen Presentation Antigens Antitubercular Agents Bacteria Biochemical C3HeB/FeJ Mouse Chemotherapy-Oncologic Procedure Dendritic Cells Disease Disease Progression Drug resistance in tuberculosis Equilibrium Extreme drug resistant tuberculosis Granuloma Granulomatous Health Human Immune Immune response Immunity Immunotherapy Infection Inflammatory Response Lesion Lung Mediating Modeling Monitor Mus Mycobacterium tuberculosis Nature Necrosis Pathology Penetration Peptide Hydrolases Pharmaceutical Preparations Pulmonary Pathology Regimen Relapse Resolution Role Serine Protease Sterilization T cell response Testing Therapeutic Time Tissues Treatment Protocols Treatment outcome Tuberculosis Virulence Factors Virulent adaptive immunity antimicrobial drug base chemotherapy extensive drug resistance immunopathology improved in vivo inhibitor/antagonist insight killings knock-down macrophage mouse model mutant novel therapeutics pathogen prevent pulmonary granuloma response small molecule inhibitor three dimensional structure treatment duration treatment effect tuberculosis treatment

项目摘要

DESCRIPTION (provided by applicant): The current regimen for treating tuberculosis (TB) involves multiple antibiotics, is long and arduous and has contributed to the emergence of drug-resistant TB. Improving anti-TB chemotherapy by shortening treatment and enhancing efficacy is therefore a high priority for global TB control. Manipulating the host immune response to reduce the harmful effects of Mtb-induced immune responses may enhance the efficacy of antibiotics. We hypothesize that blocking the functions of a key Mycobacterium tuberculosis (Mtb) immunomodulatory protease, Hip1, will create a more favorable in vivo immune milieu for resolving infection, leading to accelerated clearance of Mtb by antibiotics and shortened treatment. This concept of targeting pathogen-specific virulence factors to improve treatment outcomes has not previously been explored. Studies from our group have shown that Hip1 promotes detrimental innate and adaptive immune responses in Mtb- infected macrophages, dendritic cells and mice. Absence of Hip1 is beneficial to the host as this results in mild immunopathology and prolonged survival of infected mice despite high bacterial burdens in vivo. Thus we propose that inhibiting Hip1 is attractive for developing adjunctive immune therapeutics for TB. We will use the C3HeB/FeJ mouse model of TB chemotherapy to test the hypothesis that silencing hip1 in conjunction with anti-TB treatment will reduce pathology and tissue damage in the lung and accelerate clearance of Mtb. We propose the following proof of concept studies: Aim 1. Determine whether silencing hip1 improves clearance of Mtb during anti-TB chemotherapy in a mouse model of TB. We will infect mice with a conditional hip1 knockdown strain and assess bacterial clearance at time points following antibiotic treatment, and evaluate the occurrence of relapse compared to controls. Aim 2. Characterize the effect of hip1 silencing on lung immune responses and granulomatous pathology during chemotherapy. We will compare inflammatory responses, antigen-specific T cell responses and the nature of lung granuloma lesions induced by infection with wild type and hip1 knockdown Mtb strains before, during and after treatment. These studies will give us important insights into whether inhibition of Hip1 is a feasible approach for adjunctive immune therapy and provide a framework for testing candidate Hip1 inhibitors in vivo.

描述（由适用提供）：治疗结核病（TB）的当前方案涉及多种抗生素，漫长而艰巨，并有助于耐药结核病的出现。因此，通过缩短治疗和提高效率来改善抗TB化疗是全球结核病控制的高度优先级。操纵宿主免疫激素以减少MTB诱导的免疫反应的有害作用，可能会增强抗生素的疗效。我们假设阻止关键的结核分枝杆菌（MTB）免疫调节蛋白酶HIP1的功能将创造出一个更有利的在体内免疫环境中解决感染，从而导致抗生素和快速治疗加速MTB的清除。以前尚未探讨这种靶向病原体特异性病毒因素以改善治疗结果的概念。我们小组的研究表明，HIP1促进了MTB感染的巨噬细胞，树突状细胞和小鼠的有害先天和适应性免疫回报。 HIP1的缺乏对宿主有益，因为这会导致轻度的免疫病理学和感染小鼠的长期存活，尽管伯恩斯在体内很高。我们建议抑制HIP1对于开发TB的辅助免疫疗法具有吸引力。我们将使用TB化学疗法的C3HEB/FEJ小鼠模型来检验以下假设：沉默HIP1与抗TB治疗结合使用将减少肺中的病理和组织损伤，并加速MTB的清除。我们提出以下概念研究证明：目标1。确定在TB小鼠模型中，在抗TB化疗期间，在抗TB化疗期间，沉默HIP1是否会提高MTB的清除率。我们将在抗生素治疗后的时间点上以条件HIP1敲低菌株和评估细菌的清除感染小鼠，并评估与对照组相比的退休发生。 AIM 2。表征HIP1沉默对化学疗法期间肺部免疫调查和肉芽肿病病理学的影响。我们将比较炎症反应，抗原特异性T细胞反应以及在治疗之前，期间和治疗后，野生型和HIP1敲低MTB菌株诱导的肺肉芽肿病变的性质。这些研究将使我们对HIP1的抑制是否是辅助免疫疗法的可行方法，并为在体内测试候选HIP1抑制剂提供框架。