Regulation Of Immunopathology In Bacterial And Parasitic Disease

细菌和寄生虫病免疫病理学的调节

• 批准号: 9161516
• 负责人: Alan Sher
• 金额: $ 84.64万
• 依托单位: NATIONAL INSTITUTE OF ALLERGY AND INFECTIOUS DISEASES
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/9161516
• 关键词: Acute; Aerosols; Affect; African; Agreement; Animals; Antigens; Archives; Area; Bacterial Infections; Biological Assay; Biological Markers; Brazil; CD4 Positive T Lymphocytes; Clinical; Clinical Research; Collaborations; Dependence; Discrimination; Disease; Effector Cell; Enzymes; Experimental Animal Model; Goals; Grant; Host resistance; Human; Immune; Immune response; Immunity; Immunologics; Immunotherapeutic agent; In Vitro; India; Individual; Infection; Infectious Agent; Interleukin-12; Interstitial Collagenase; Intervention; Joints; Knockout Mice; Lung; Lung diseases; Macaca; Matrix Metalloproteinases; Measurement; Measures; Minor; Modeling; Monkeys; Mus; Mycobacterium avium-intracellulare Infection; Mycobacterium tuberculosis; Outcome; Oxidative Stress; Parasitic Diseases; Pathogenesis; Pathology; Patients; Pharmaceutical Preparations; Phase; Plasma; Process; Production; Publishing; Pulmonary Tuberculosis; Pyrazinamide; Regimen; Regulation; Reporting; Rifampin; Role; Scientific Advances and Accomplishments; South Africa; Spleen; Staging; Structure of parenchyma of lung; T-Lymphocyte; T-Lymphocyte Subsets; Testing; Time; Transgenic Organisms; Tuberculosis; United States National Institutes of Health; Universities; Work; antioxidant enzyme; chemokine; chemotherapy; clinical Diagnosis; cohort; cytokine; heme oxygenase-1; human disease; immunopathology; inhibitor/antagonist; macrophage; mouse model; pathogen; prevent; research study; response; therapy design; tuberculosis drugs; tuberculosis treatment

Pulmonary tuberculosis (TB) is characterized by oxidative stress and lung tissue destruction by matrix metalloproteinases. The relationship between these distinct processes and the implications for TB diagnosis and clinical disease staging are poorly understood. Our work in this area has focused on the interplay between the anti-oxidant enzyme heme oxygenase-1 (HO-1) and matrix metalloproteinases (MMPs) in human and experimental TB infection. As described in last years report and now published on-line (see Scientific Advance), Bruno Andrade and our clinical colleagues in India, Brazil and the NIH demonstrated that patients with TB (but not healthy controls or individuals with latent TB infection) express either very high levels of HO-1 or of MMP-1. They also showed that production of the two enzymes is cross-regulated in human macrophages infected with Mtb in vitro. Together their studies argued that combined measurement of HO-1 and MMP-1 offers a strategy both for discrimination of active TB from other lung diseases and for clinical staging of TB patients. In this years work (supported in part by a joint US-South Africa UO-1 grant) we have extended this analysis to a larger, better characterized archived cohort in Cape Town and to a new treatment cohort being initiated as a major component of the UO-1 project. The aim will be to both further validate our initial findings in a geographically distinct African patient group and to more definitively explore the relationship of biomarker expression with clinical disease. At the same time we have initiated new studies with Mtb experimental animal models to examine the function of HO-1 and MMP-1 in both host resistance and pathology. In collaboration with Chuck Scanga and Joanne Flynn (University of Pittsburgh) we measured the two markers in plasma of Mtb infected cynomolgus macaques and in the case of HO-1 observed a close association of enzyme expression and infection progression which was reduced upon treatment. A less consistent correlation with active infection was observed when MMP-1 expression was measured in the same monkeys, nor did combined assay of HO-1 and MMP-1 reveal any disease correlations in the limited number of animals studied so far. We also initiated experiments in the mouse model to assess the role of HO-1 in MTb induced host resistance. Interestingly, administration of an HO-1 inhibitor (SnPP) was found to induce a highly significant reduction in bacterial load in aerosol infected MTb infected mice and to enhance the effects of chemotherapy when given together with a standard TB drug regimen. This effect was observed only when the inhibitor was administered to established infections as the drug failed to block new infection. Together these experiments suggest that HO-1 might be a useful target for host-directed therapy of tuberculosis. A major ongoing project in the lab has been to investigate the role of the host immune response in chemotherapy of tuberculosis and in particular the involvement of T cell dependent immunity. Studies by Diego Costa using T cell deficient TCR alpha knock-out mice indicated that standard TB drug treatment with isoniaizid, rifampicin and pyrazinamide (HRZ) causes a similar reduction in pulmonary bacterial load whether or not T cells are present with only a minor delay in final bacillary clearance. Similarly, attempts to enhance treatment by simultaneous administration of transgenic CD4+ T cells recognizing important TB antigens so far yielded negative results. In parallel experiments, we tested the effects of adjunct administration of IL-12, a cytokine required for both acute control of TB infection and the Th1 response to the pathogen on the outcome of chemotherapy. Again, this immunotherapeutic intervention failed to significantly effect drug induced bacterial control in the lungs but in agreement with previously published work in the lab on Mycobacterium avium infection significantly reduced disseminated infection measure in spleen. These results taken together with other experiments examining the immune dependence of chemotherapy in the mouse model suggest that drug induced clearance Mtb in the lungs during the early intensive phase is not significantly affected by either the endogenous cellular immune response or by exogenous administration of cytokines, or for that matter, TB effector cells themselves.

肺结核（TB）的特征是基质金属蛋白酶氧化应激和肺组织破坏。这些独特的过程之间的关系以及对结核病诊断和临床疾病分期的影响鲜为人知。我们在这一领域的工作集中在人和实验性结核病感染中抗氧化酶血红素氧酶-1（HO-1）和基质金属蛋白酶（MMP）之间的相互作用。如去年报告中所述，现在在线发表（请参阅科学进展），布鲁诺·安德拉德（Bruno Andrade）以及我们在印度，巴西和NIH的临床同事表明，患有结核病患者（但不是健康的对照组或潜在结核病感染），表达了很高的HO-1或MMP-1的水平。他们还表明，在体外感染了MTB的人类巨噬细胞中，这两种酶的产生在体外进行了交叉调节。他们的研究共同认为，HO-1和MMP-1的合并测量提供了一种策略，既可以歧视其他肺部疾病的主动结核病，又可以歧视结核病患者的临床分期。在今年的工作中（部分由美国南非联合的UO-1赠款支持），我们将这项分析扩展到开普敦的更大，更具特征性的存档队列，并将作为UO-1项目的主要组成部分启动了新的治疗群体。目的是进一步验证我们在地理上不同的非洲患者群体中的初步发现，并更明确地探索生物标志物表达与临床疾病的关系。 同时，我们开始使用MTB实验动物模型进行新的研究，以检查HO-1和MMP-1在宿主抗性和病理学中的功能。与Chuck Scanga和Joanne Flynn（匹兹堡大学）合作，我们测量了MTB感染的Cynomolgus Macaques的血浆中的两个标记，而HO-1的情况下观察到酶表达和感染进展的紧密关联，从治疗后降低了。 当在同一猴子中测量MMP-1表达时，观察到与主动感染的一致相关性较小，而HO-1和MMP-1的合并测定也没有发现迄今为止研究的有限动物中的任何疾病相关性。我们还在小鼠模型中启动了实验，以评估HO-1在MTB诱导的宿主电阻中的作用。有趣的是，发现施用HO-1抑制剂（SNPP）可引起气雾剂感染的MTB感染小鼠的细菌负荷降低，并与标准的TB药物治疗疗法一起进行化学疗法的影响。仅当药物未能阻止新的感染而将抑制剂施用到已建立的感染时，才能观察到这种作用。这些实验共同表明，HO-1可能是宿主定向的结核病治疗的有用靶标。 实验室中的一个主要项目是研究宿主免疫反应在结核病化疗中的作用，尤其是T细胞依赖性免疫的参与。迭戈·科斯塔（Diego Costa）使用TCR缺乏TCRα敲除小鼠进行的研究表明，标准的TB药物治疗等氧化物，利福平和吡嗪酰胺（HRZ）会导致肺部细菌负荷的类似降低，无论是否仅在最终的细菌清除率中延迟较小的T细胞。同样，尝试通过同时给予识别重要结核抗原的转基因CD4+ T细胞来增强治疗的尝试产生了阴性结果。在并行实验中，我们测试了IL-12辅助施用的影响，IL-12是TB感染的急性控制和TH1对病原体的反应对化疗结果所需的细胞因子。同样，这种免疫治疗干预措施未能显着影响药物诱导的肺部细菌对照，但与先前在实验室中关于硫分枝杆菌感染的作品一致，可显着降低脾脏中的传播感染测量。这些结果与研究小鼠模型中化学疗法的免疫依赖性的其他实验一起表明，在早期强度阶段，药物诱导的清除率MTB在肺中没有受到内源性细胞免疫反应或外源性细胞因子的给药的显着影响，或者在此问题上，TB效应细胞本身。