TB Meningitis: Evaluating CSF Immunology to Discover Hidden Disease and Potential Immunomodulatory Therapies

结核性脑膜炎：评估脑脊液免疫学以发现隐藏疾病和潜在的免疫调节疗法

• 批准号: 10675513
• 负责人: David R Boulware
• 金额: $ 66.07万
• 依托单位: UNIVERSITY OF MINNESOTA
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-08-01 至 2026-07-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10675513
• 关键词: AIDS related cancer; Acid Fast Bacillae Staining Method; Acquired Immunodeficiency Syndrome; Address; Adrenal Cortex Hormones; Adult; Africa South of the Sahara; Anti-Inflammatory Agents; Autopsy; Bacillus; Bacteria; Biological; Biological Markers; Brain; CXCR3 gene; Caring; Cell Lineage; Cells; Cerebrospinal Fluid; Cessation of life; Characteristics; Clinical; Clinical Research; Clinical Trials; Color; Data; Diagnosis; Diagnostic Sensitivity; Diagnostic tests; Disease; Disease Outcome; Dose; Enrollment; Flow Cytometry; HIV; HIV Seronegativity; Human; Immune; Immune response; Immunity; Immunologic Deficiency Syndromes; Immunologics; Immunology; Immunotherapy; Infection; Infection Control; Inflammation; Inflammatory Response; Interferons; Interleukin-6; Knowledge; Medical; Meningeal Tuberculosis; Meningitis; Methodology; Methods; Microscopy; Minnesota; Morbidity - disease rate; Mycobacterium tuberculosis; Neurocognitive; Oral; Outcome; Pathogenesis; Pathologic; Patients; Persons; Pharmacotherapy; Phase; Phenotype; Play; Publishing; Research; Research Infrastructure; Rifampin; Sampling; Site; Specimen; Steroids; T-Lymphocyte; TNF gene; Testing; Tissues; Translational Research; Tuberculosis; Tuberculous Pericarditis; Uganda; Vulnerable Populations; Work; chemokine; clinical care; cytokine; experience; follow-up; high risk; immune activation; immune function; immunomodulatory therapies; improved; innovation; mortality; neurocognitive test; neutrophil; phase II trial; phase III trial; prospective; randomized, clinical trials; recruit; response; skills; survival outcome; targeted treatment; trafficking; treatment optimization; treatment response; AIDS related cancer; Acid Fast Bacillae Staining Method; Acquired Immunodeficiency Syndrome; Address; Adrenal Cortex Hormones; Adult; Africa South of the Sahara; Anti-Inflammatory Agents; Autopsy; Bacillus; Bacteria; Biological; Biological Markers; Brain; CXCR3 gene; Caring; Cell Lineage; Cells; Cerebrospinal Fluid; Cessation of life; Characteristics; Clinical; Clinical Research; Clinical Trials; Color; Data; Diagnosis; Diagnostic Sensitivity; Diagnostic tests; Disease; Disease Outcome; Dose; Enrollment; Flow Cytometry; HIV; HIV Seronegativity; Human; Immune; Immune response; Immunity; Immunologic Deficiency Syndromes; Immunologics; Immunology; Immunotherapy; Infection; Infection Control; Inflammation; Inflammatory Response; Interferons; Interleukin-6; Knowledge; Medical; Meningeal Tuberculosis; Meningitis; Methodology; Methods; Microscopy; Minnesota; Morbidity - disease rate; Mycobacterium tuberculosis; Neurocognitive; Oral; Outcome; Pathogenesis; Pathologic; Patients; Persons; Pharmacotherapy; Phase; Phenotype; Play; Publishing; Research; Research Infrastructure; Rifampin; Sampling; Site; Specimen; Steroids; T-Lymphocyte; TNF gene; Testing; Tissues; Translational Research; Tuberculosis; Tuberculous Pericarditis; Uganda; Vulnerable Populations; Work; chemokine; clinical care; cytokine; experience; follow-up; high risk; immune activation; immune function; immunomodulatory therapies; improved; innovation; mortality; neurocognitive test; neutrophil; phase II trial; phase III trial; prospective; randomized, clinical trials; recruit; response; skills; survival outcome; targeted treatment; trafficking; treatment optimization; treatment response

Abstract In Sub-Saharan Africa, tuberculous meningitis (TBM) is the second most common cause of adult meningitis, and a major cause of morbidity and mortality among people living with HIV. While host immuno- deficiency clearly drives TBM pathogenesis, pathologic immune responses can also worsen disease. The key drivers of HIV-associated TBM pathogenesis remain undefined but likely differ from HIV-negative TBM, thus a study of the pathogenesis of TBM in HIV-infected humans is warranted and innovative. Opportunities for host-directed therapy in this vulnerable population remain unexplored. To optimize treatment of HIV/TBM and improve survival, it is critical to fully characterize host responses at the site of infection and identify immune signatures associated with good or poor outcomes. To this challenge, we bring our skills in experimental immunology of tuberculosis, matched with an experienced research team with a proven track record of clinical and translational research regarding AIDS-related meningitis in Uganda. Diagnosing TBM is notoriously difficult. The poor sensitivity (~50%) of standard methodologies detects only a subset of those with TBM, likely with the highest CSF bacillary burden. In these patients hypo-functional or pathologic immune responses, representing opposite extremes of immune function, may contribute to poor host control of infection. The higher sensitivity of Xpert Ultra enables semi-quantitative diagnosis of those with a lower burden of CSF bacteria and identifies a group with better immune control of the infection. Our preliminary data suggest that diagnosis with trace or very low Xpert Ultra is associated with better survival. In this project, we propose a new microbiologic/immunologic framework for understanding TBM, categorizing patients based on the differing Xpert Ultra PCR cycle-threshold, which serve as a surrogate for CSF bacterial burden. We seek to interrogate this framework by defining disease outcomes including survival and neurocognitive testing in these different framework groups, while correlating these findings with immunologic analyses of cellular immune responses in the CSF. Our central hypothesis is that CSF immune signatures correlate with key aspects of TBM disease pathogenesis including sensitivity of diagnostics, disease outcomes, and treatment responses. To test this, we will perform high parameter spectral flow cytometry and multiplex cytokine profiling of samples from the CSF and autopsy specimens of patients with HIV/TBM. By comparing these comprehensive immunologic data in groups of patients with either high or low CSF bacterial burden, in those with good or poor outcomes, and in the context of a clinical trial of standard vs high dose rifampin treatment, we aim to define the key contributions of host immunity to TBM pathogenesis. If our hypothesis is correct, the implications of this research are that immunomodulatory therapy will need to be customized to address the paucity or excess of immune responses.

抽象的 在撒哈拉以南非洲，结核性脑膜炎（TBM）是成人的第二大最常见原因 脑膜炎以及艾滋病毒患者发病和死亡的主要原因。而主机免疫 - 缺乏显然会驱动TBM发病机理，病理免疫反应也会恶化疾病。钥匙 HIV相关的TBM发病机理的驱动因素仍然不确定，但可能与HIV阴性TBM不同，因此A 有必要和创新的HIV感染人类中TBM发病机理的研究。 在这一脆弱人群中进行宿主定向治疗的机会尚未得到探索。优化 艾滋病毒/TBM的治疗并提高生存率，至关重要的是完全表征宿主的反应 感染并确定与良好或不良结局相关的免疫特征。为了挑战，我们带来 我们在结核病实验免疫学方面的技能，与经验丰富的研究团队相匹配 关于乌干达艾滋病相关脑膜炎的临床和转化研究的可靠记录。 众所周知，诊断TBM是困难的。标准方法的敏感性不佳（〜50％）可检测到 患有TBM的人的子集，可能具有最高的CSF细菌负担。在这些患者中，功能低下或 病理免疫反应，代表相反的免疫功能的极端，可能导致不良 感染的宿主控制。 Xpert Ultra的较高灵敏度可以使患有的人的半定量诊断 CSF细菌的负担较低，并确定了对感染更好免疫控制的一组。我们的 初步数据表明，痕量或非常低的Xpert Ultra诊断与更好的生存有关。 在这个项目中，我们提出了一个新的微生物/免疫学框架，以了解TBM， 根据不同的XPERT Ultra PCR周期阈值对患者进行分类，该阈值是 CSF细菌负担。我们试图通过定义包括生存在内的疾病结局来审问这一框架 以及这些不同框架组中的神经认知测试，同时将这些发现与 CSF中细胞免疫反应的免疫学分析。 我们的中心假设是CSF免疫特征与TBM疾病的关键方面相关 发病机理，包括诊断，疾病结局和治疗反应的敏感性。为了测试这一点，我们 将执行来自CSF的样品的高参数流式细胞仪和多重细胞因子分析 和HIV/TBM患者的尸检标本。通过比较这些全面的免疫数据 csf细菌负担高或低的患者，在良好或差的患者中， 标准与高剂量利福平治疗的临床试验的背景，我们旨在定义关键贡献 宿主对TBM发病机理的免疫力。如果我们的假设是正确的，那么这项研究的含义是 需要定制免疫调节疗法，以解决免疫反应的匮乏或过度。