Cellular and molecular architecture of granulomas in human tuberculous lymphadenitis

人结核性淋巴结炎肉芽肿的细胞和分子结构

• 批准号: 10666864
• 负责人: Chaouki Benabdessalem
• 金额: $ 14.72万
• 依托单位: INSTITUT PASTEUR DE TUNIS
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-05-01 至 2028-04-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10666864
• 关键词: Acute; Affect; Antigens; Architecture; Bacillus; Bacteria; Biological Markers; Biopsy; Chronic; Chronic Disease; Clinical; Collaborations; Collection; Cytotoxic T-Lymphocytes; Data; Diagnosis; Diagnostic; Disease; Ensure; Etiology; Gene Expression; Genes; Granuloma; Health; Healthcare Systems; Histologic; Host Defense; Host Defense Mechanism; Human; Immune; Immune response; Immunocompromised Host; Immunologic Markers; Individual; Infection; Infection Control; Inflammation; Inflammatory Response; Interferons; Invaded; Leprosy; Ligands; Location; Lung; Lymph Node Tuberculosis; Lymphocyte; Macrophage; Macrophage Activation; Maps; Measures; Mediator; Microscopy; Modality; Molecular; Mycobacterium Infections; Mycobacterium bovis; Mycobacterium tuberculosis; Organ; Pathologic; Pathway interactions; Patient Care; Patients; Pulmonary Tuberculosis; Pyrazinamide; Research Training; Resistance; Scientist; Site; Spatial Distribution; Specimen; T cell response; T-Lymphocyte; Technology Transfer; Testing; Therapeutic; Tissues; Tuberculosis; Tunisia; antimicrobial; antimicrobial peptide; biomarker identification; biosignature; cell type; clinical care; cytokine; data integration; granulysin; improved; insight; lymph nodes; microbicide; molecular marker; mycobacterial; pathogen; peripheral blood; radiological imaging; response; single-cell RNA sequencing; technology training; transcriptomics; tuberculosis granuloma

ABSTRACT Tuberculous lymphadenitis (TBL) is the most frequent form of extrapulmonary of TB affecting approximately 2000 individuals in Tunisia annually, such that the disease is a clinical burden on the Tunisian health care system. Since the occurrence of concomitant pulmonary TB in TBL patients is infrequent, and bacilli are rarely detected by microscopy, TBL represents a form of TB in which the infection is controlled and not yet disseminated, except in immunocompromised individuals. TBL in Tunisia is generally caused by Mycobacterium bovis or M. tuberculosis, yet cannot be distinguished clinically, radiographically, or pathologically. The histologic hallmark of TB is the granuloma, an organized collection of macrophages, lymphocytes, and other cell types that function to contain and kill invading pathogens. Here, we will test the hypothesis that elucidation of the cellular and molecular architecture of TBL granulomas will lead to the identification of disease biomarkers and insight into the mechanisms by which T cell responses regulates antimicrobial responses in granulomas. We propose to study the cellular and molecular architecture of granulomas in TBL by integrating single cell RNA-sequencing (scRNA-seq) with spatial-seq of lymph node specimens that are obtained as part of routine clinical care. This project brings together scientists from the Benabdessalem lab at the Institut Pasteur de Tunis (IPT) with scientists from UCLA, who have already collaborated to generate preliminary data measuring the spatial distribution of cell types and genes in pulmonary TB and TBL granulomas. In Aim 1, we will determine the cellular and molecular architecture of TBL granulomas, identifying biomarkers related to antimicrobial responses that correlate with the causative agent, M. bovis vs. M. tuberculosis, as well as comparing the response in TBL to pulmonary TB. In Aim 2, we will determine the contribution of T cells to control the infection in TBL granulomas through antimicrobial responses, including relevant correlates to specific mycobacterial antigens in peripheral blood. Together, these studies will provide new insight into the mechanisms by which the intersection of T cell responses and granuloma organization impacts host control of M. bovis vs. M. tuberculosis infection. As such, our studies of the specific immune biosignatures in TBL will expand our understanding of its immunopathogenesis, leading to improved care for patients with TBL. An important part of this application is to ensure transfer of technology and research training from the Modlin lab at UCLA to the Benabdessalem lab at IPT.

抽象的 结核性淋巴结炎 (TBL) 是肺外结核最常见的形式，影响约 突尼斯每年有 2000 人感染该病，该病已成为突尼斯卫生保健的临床负担 系统。由于TBL患者并发肺结核的情况很少见，而且杆菌也很少见。 通过显微镜检测，TBL 代表结核病的一种形式，其中感染已得到控制但尚未得到控制 传播，但免疫功能低下的个体除外。突尼斯的 TBL 通常是由以下原因引起的 牛分枝杆菌或结核分枝杆菌，但无法通过临床、放射学或 病理上。结核病的组织学标志是肉芽肿，是巨噬细胞的有组织集合， 淋巴细胞和其他具有遏制和杀死入侵病原体的细胞类型。在这里，我们将测试 假设阐明 TBL 肉芽肿的细胞和分子结构将导致 识别疾病生物标志物并深入了解 T 细胞反应调节机制 肉芽肿的抗菌反应。我们建议研究细胞和分子结构 通过将单细胞 RNA 测序 (scRNA-seq) 与淋巴结空间序列相结合来检测 TBL 中的肉芽肿 作为常规临床护理的一部分获得的标本。该项目汇集了来自各个领域的科学家 突尼斯巴斯德研究所 (IPT) 的 Benabdessalem 实验室与加州大学洛杉矶分校的科学家合作，他们已经 合作生成测量细胞类型和基因空间分布的初步数据 肺结核和 TBL 肉芽肿。在目标 1 中，我们将确定 TBL 的细胞和分子结构 肉芽肿，识别与病原体相关的抗菌反应相关的生物标志物， 牛分枝杆菌与结核分枝杆菌，以及比较 TBL 对肺结核的反应。在目标 2 中，我们将 确定 T 细胞通过抗菌药物控制 TBL 肉芽肿感染的作用 反应，包括与外周血中特定分枝杆菌抗原的相关性。在一起，这些 研究将为 T 细胞反应和 T 细胞反应交叉的机制提供新的见解。 肉芽肿组织影响宿主对牛分枝杆菌与结核分枝杆菌感染的控制。因此，我们的研究 TBL 中的特异性免疫生物特征将扩大我们对其免疫发病机制的理解，从而导致 改善 TBL 患者的护理。该应用程序的一个重要部分是确保技术转让 以及从加州大学洛杉矶分校 Modlin 实验室到 IPT Benabdessalem 实验室的研究培训。