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

• 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
• 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

 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（由申请人提供）：目前治疗结核病（TB）的方案涉及多种抗生素，时间长且费力，并导致耐药结核病的出现。因此，通过缩短治疗时间和提高疗效来改进抗结核化疗是全球结核病控制的一个高度优先事项。操纵宿主免疫应答以减少结核分枝杆菌诱导的免疫应答的有害影响可以增强抗生素的功效。我们假设，阻断结核分枝杆菌（Mtb）免疫调节蛋白酶Hip 1的功能，将为解决感染创造更有利的体内免疫环境，从而加速抗生素对Mtb的清除并缩短治疗时间。这种靶向病原体特异性毒力因子以改善治疗结果的概念以前尚未被探索过。我们小组的研究表明，Hip 1在结核分枝杆菌感染的巨噬细胞、树突状细胞和小鼠中促进有害的先天性和适应性免疫应答。缺乏Hip 1对宿主有益，因为这导致轻度免疫病理学和感染小鼠的存活期延长，尽管体内细菌负荷高。因此，我们认为抑制Hip 1对于开发结核病的连续免疫疗法具有吸引力。我们将使用结核病化疗的C3 HeB/FeJ小鼠模型来检验以下假设：沉默hip 1与抗结核治疗结合将减少肺中的病理和组织损伤并加速Mtb的清除。我们提出以下概念验证研究：目标1。确定沉默hip 1是否改善结核病小鼠模型中抗结核化疗期间Mtb的清除。我们将用条件性hip 1敲低菌株感染小鼠，并在抗生素治疗后的时间点评估细菌清除率，并与对照组相比评估复发的发生率。目标2.描述hip 1沉默对化疗期间肺免疫应答和肉芽肿病理学的影响。我们将比较炎症反应，抗原特异性T细胞反应和肺肉芽肿病变的性质与野生型和hip 1敲低结核分枝杆菌菌株感染前，治疗期间和治疗后。这些研究将为我们提供重要的见解，以了解抑制Hip 1是否是一种可行的免疫治疗方法，并为体内测试候选Hip 1抑制剂提供了一个框架。