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.

抽象的 在撒哈拉以南非洲地区，结核性脑膜炎 (TBM) 是成人第二大常见原因 脑膜炎，也是艾滋病毒感染者发病和死亡的主要原因。当宿主免疫 缺陷明显驱动了 TBM 发病机制，病理性免疫反应也会使疾病恶化。关键 HIV 相关 TBM 发病机制的驱动因素仍未明确，但可能与 HIV 阴性 TBM 不同，因此 对 HIV 感染者 TBM 发病机制的研究是必要且具有创新性的。 在这一弱势群体中进行宿主导向治疗的机会仍有待探索。优化 治疗 HIV/TBM 并提高生存率，充分描述感染部位的宿主反应至关重要 感染并识别与良好或不良结果相关的免疫特征。为了应对这一挑战，我们带来了 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 乌干达艾滋病相关脑膜炎临床和转化研究的可靠记录。 诊断 TBM 非常困难。标准方法的灵敏度较差（~50%），仅检测到 TBM 患者的一个子集，可能具有最高的脑脊液细菌负荷。在这些患者中，功能低下或 病理性免疫反应代表免疫功能的相反极端，可能导致不良反应 宿主对感染的控制。 Xpert Ultra 具有更高的灵敏度，可以对患有以下疾病的患者进行半定量诊断 脑脊液细菌负担较低，并确定了对感染具有更好免疫控制能力的群体。我们的 初步数据表明，微量或非常低的 Xpert Ultra 诊断与更好的生存率相关。 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 Ultra PCR 循环阈值对患者进行分类，该阈值可作为替代 脑脊液细菌负荷。我们试图通过定义包括生存在内的疾病结果来质疑这个框架 和这些不同框架组中的神经认知测试，同时将这些发现与 脑脊液中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特征与 TBM 疾病的关键方面相关 发病机制，包括诊断的敏感性、疾病结果和治疗反应。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 以及 HIV/TBM 患者的尸检标本。通过比较这些综合免疫学数据 脑脊液细菌负荷高或低、预后良好或不良的患者组以及 在标准剂量与高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贡献 宿主免疫对 TBM 发病机制的影响。如果我们的假设是正确的，那么这项研究的意义在于 免疫调节疗法需要进行定制，以解决免疫反应不足或过度的问题。