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: 10459614
• 负责人: David R Boulware
• 金额: $ 67.08万
• 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/10459614
• 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 Markers; Brain; CXCR3 gene; Caring; Cell Lineage; Cells; Cerebrospinal Fluid; Cessation of life; Characteristics; Clinical; Clinical Research; Clinical Trials; Color; Custom; 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-1; Interleukin-6; Knowledge; Medical; Meningeal Tuberculosis; Meningitis; Methodology; Methods; Microbiology; Microscopy; Minnesota; Morbidity - disease rate; Mycobacterium tuberculosis; Neurocognitive; Oral; Outcome; Pathogenesis; Pathologic; Patients; Pericarditis; Persons; Phase; Phenotype; Play; Publishing; Randomized Clinical Trials; Research; Research Infrastructure; Rifampin; Sampling; Site; Specimen; Steroids; T-Lymphocyte; TNF gene; Testing; Tissues; Translational Research; Tuberculosis; Uganda; Vulnerable Populations; Work; base; 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; 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.

摘要 在撒哈拉以南非洲，结核性脑膜炎(TBM)是成人的第二大常见原因 脑膜炎是艾滋病毒携带者发病和死亡的主要原因。当宿主免疫时- 缺乏明显推动了TBM的发病，病理性免疫反应也会使疾病恶化。钥匙 HIV相关的TBM的发病机制仍未明确，但可能与HIV阴性的TBM不同，因此 对HIV感染者的TBM发病机制的研究是有必要的和创新的。 在这一脆弱人群中进行宿主导向治疗的机会仍未被探索。要优化 为了治疗HIV/TBM并提高存活率，关键是要充分描述宿主在 感染，并确定与预后好坏相关的免疫特征。面对这一挑战，我们带来了 我们在结核病的实验免疫学方面的技能，与经验丰富的研究团队相匹配，具有 在乌干达关于艾滋病相关脑膜炎的临床和转译研究的可靠记录。 诊断TBM是出了名的困难。标准方法的低灵敏度(~50%)仅检测 脑脊液细菌负荷最高的脑脊液结核患者的一部分。在这些患者中，功能低下或 病理性免疫反应代表了免疫功能的两个极端，可能导致不良反应。 宿主对感染的控制。Xpert Ultra的较高灵敏度使患者能够进行半定量诊断 脑脊液细菌的负担较低，并确定了对感染有更好免疫控制的一组。我们的 初步数据表明，诊断为微量或极低的Xpert Ultra与更好的生存相关。 在这个项目中，我们提出了一个新的微生物学/免疫学框架来理解TBM， 根据不同的Xpert超级聚合酶链式反应周期阈值对患者进行分类，该阈值可作为 脑脊液细菌负荷。我们试图通过定义包括存活在内的疾病结果来询问这一框架。 在这些不同的框架组进行神经认知测试，同时将这些发现与 脑脊液细胞免疫反应的免疫学分析。 我们的中心假设是脑脊液免疫信号与脑脊液疾病的关键方面相关。 发病机制包括诊断、疾病结果和治疗反应的敏感性。为了测试这一点，我们 将对脑脊液样本进行高参数光谱流式细胞术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学数据 脑脊液细菌负荷高或低的患者组，预后良好或差的患者组，以及 在标准剂量与大剂量利福平治疗的临床试验的背景下，我们的目标是确定关键的贡献 宿主免疫对TBM发病的影响。如果我们的假设是正确的，这项研究的含义是 免疫调节疗法将需要定制，以解决免疫反应不足或过剩的问题。