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.

摘要 结核性淋巴结炎（TBL）是肺外结核最常见的形式， 每年在突尼斯有2000人，因此该疾病是突尼斯卫生保健的临床负担 系统由于TBL患者合并肺结核的发生率很低， 通过显微镜检测，TBL代表了一种结核病，其中感染得到控制， 除免疫功能低下者外，其他均为播散性。突尼斯的TBL通常由以下原因引起： 牛分枝杆菌或M.结核病，但不能区分临床，放射学，或 病态地。结核病的组织学标志是肉芽肿，一种有组织的巨噬细胞聚集， 淋巴细胞和其他细胞类型，其功能是遏制和杀死入侵的病原体。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细胞反应调节的机制 肉芽肿中的抗菌反应。我们建议研究的细胞和分子结构的 通过整合淋巴结的单细胞RNA测序（scRNA-seq）和空间测序， 作为常规临床护理的一部分获得的标本。该项目汇集了来自世界各地的科学家， 突尼斯巴斯德研究所（IPT）的Benabdessalem实验室与来自加州大学洛杉矶分校的科学家，他们已经 合作产生初步数据，测量细胞类型和基因的空间分布， 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，鉴定与病原体相关的抗微生物应答相关的生物标志物， M. bovis与M.结核病，以及比较TBL对肺结核的反应。在目标2中，我们将 确定T细胞通过抗微生物药物控制TBL肉芽肿感染的作用， 应答，包括与外周血中特异性分枝杆菌抗原的相关性。所有这些 这些研究将为T细胞反应和免疫应答的交叉机制提供新的见解。 肉芽肿组织影响宿主对M. bovis与M.肺结核感染。因此，我们的研究 TBL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， 改善TBL患者的护理。这项申请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的莫德林实验室到IPT的贝纳布德萨勒姆实验室的研究培训。