Type II alveolar epithelial cell-intrinsic IL-1 response in protective immunity against tuberculosis

II 型肺泡上皮细胞内在 IL-1 反应在结核病保护性免疫中的作用

• 批准号: 10660267
• 负责人: Bibhuti Bhusan Mishra
• 金额: $ 44.47万
• 依托单位: ALBANY MEDICAL COLLEGE
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-06-01 至 2027-05-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10660267
• 关键词: Aerosols; Affect; Alveolar; Animals; Anti-Bacterial Agents; Antibiotic Therapy; Antibodies; Antimycobacterial Agents; Bacteria; Body Weight decreased; Bone Marrow; Bone Marrow Cells; COVID-19 pandemic; Caring; Cells; Chimera organism; Clinical; Communicable Diseases; Communication; Dinoprostone; Disease; Disease Progression; Dose; Endothelial Cells; Epithelial Cells; Epithelium; Family; Genetic; Genetic Polymorphism; Grant; Granulocyte-Macrophage Colony-Stimulating Factor; Hematopoietic; Host Defense; Human; IL1R1 gene; Immune; Immune response; Immunity; Impairment; Inflammation; Inflammatory; Interferons; Interleukin-1; Interleukin-1 Receptors; Interleukin-1 alpha; Interleukin-1 beta; Knock-in; Knock-in Mouse; Knock-out; Knockout Mice; Knowledge; Laboratories; Lung; Lung infections; Macrophage; Mediating; Morbidity - disease rate; Mouse Strains; Mus; Mycobacterium tuberculosis; Myeloid Cells; National Institute of Allergy and Infectious Disease; Natural regeneration; Neutrophil Infiltration; PECAM1 gene; PTPRC gene; Pathogenicity; Pathologic; Patients; Phenocopy; Play; Predisposition; Preparation; Production; Progressive Disease; Public Health; Pulmonary Pathology; Pulmonary Tuberculosis; Radiation Tolerance; Reporter; Research; Resistance; Respiratory physiology; Risk; Role; Sampling; Severity of illness; Signal Transduction; Stromal Cells; TACSTD1 gene; Testing; Therapeutic; Tissues; Tuberculosis; Vaccines; Wasting Syndrome; airway epithelium; alveolar epithelium; antimicrobial; bacterial fitness; cell type; cytokine; design; epithelial repair; epithelium regeneration; experimental study; human disease; immunopathology; innate immune mechanisms; lung injury; member; mortality; neutrophil; pharmacologic; preservation; prevent; progenitor; pulmonary function; quantitative imaging; receptor; reconstitution; regeneration following injury; repaired; response; restraint; self-renewal; single-cell RNA sequencing; stem cell function; tuberculosis immunity

PROJECT SUMMARY/ABSTRACT Interleukin-1 (IL-1) plays an important role in the host defense against Mycobacterium tuberculosis (Mtb), the bacterium that causes human disease tuberculosis (TB). IL-1 is essential for anti-bacterial immunity during Mtb infection in mice and genetic polymorphisms in IL-1 receptor (IL-1R1) signaling are associated with greater risk from active pulmonary TB. IL-1R1 is expressed by both the hematopoietic-derived and stromal cells in the lung, but the cell-type specific roles of IL-1R1-signaling in protective immunity against TB remains unclear. Supported by a R56 Bridge grant from NIAID, we investigated the contribution of different lung cells to the IL- 1R1 mediated protective immunity. We used bone marrow chimaeras and discovered that IL-1R1 expression on stromal cells is crucial for protecting mice against severe disease. We generated a panel of knock-in and knock out mouse strains where IL-1R1 expression is conditionally deleted- or restored in specific cells either in a wild type or IL-1R1-deficient host background. Our preliminary results indicated that expression of IL-1R1 on type II alveolar epithelial cells (AECII) is both necessary and sufficient for controlling bacterial replication, inflammation in the lung and preventing wasting disease. AECII-intrinsic IL-1R1 signaling is critical for anti- mycobacterial immunity and preventing type I IFN (IFN-I) dependent neutrophil influx. Depleting neutrophils or IFN-I significantly reduced bacterial load, immunopathology. Moreover, AECII-restricted overproduction of GM- CSF in the lung protected the highly susceptible GM-CSF deficient animals by reducing bacterial load, weight loss and lung pathology. Importantly, IFN-I blockade rescued alveolar type I (AEC-I) and type II (AECII) epithelial cells that were otherwise damaged during progressive disease. Based on our preliminary results, we hypothesize that IL-1R1 signaling in AECII potentiates the anti-microbial function of myeloid cells by GM-CSF production and restrains the pathological level of IFN-I production to maintain epithelial barrier integrity. We have three specific aims. In aim1, we will investigate the role of GM-CSF in regulating antimicrobial immunity by examining bacterial fitness and replication dynamics in myeloid cells obtained from mice that lack or express IL-1R1 expression in AECII. In aim2, we will investigate the role of AECII-derived prostaglandin E2 (PGE2) in regulating IFN-I response and consequent pathogenic neutrophil influx to prevent tissue damage. Finally, in aim3, we will investigate the impact of IFN-I on alveolar epithelial cell repair and regeneration by performing lineage tracing and spatial analysis of lung epithelial cells in the infected lung samples. Overall, the completion of these aims will provide mechanistic basis for IL-1R1 mediated protective immunity and reveal principles to target airway epithelial cells for boosting antimicrobial immunity and limiting the inexorable lung damage caused during TB that contributes to lung function impairment in patients even after antibiotic therapy.

项目摘要/摘要 白介素-1（IL-1）在宿主防御结核分枝杆菌（MTB）中起着重要作用 引起人类疾病结核病（TB）的细菌。 IL-1对于MTB期间的抗细菌免疫至关重要 小鼠感染和IL-1受体（IL-1R1）信号传导中的遗传多态性与更大的风险相关 来自活性肺结核。 IL-1R1由肺中的造血细胞和基质细胞表达 但是IL-1R1信号在防护性TB中的细胞类型特异性作用尚不清楚。 在NIAID的R56桥拨款的支持下，我们研究了不同肺部细胞对IL-的贡献 1R1介导的保护性免疫。我们使用了骨髓嵌合体，发现IL-1R1表达 在基质细胞上对于保护小鼠免受严重疾病至关重要。我们产生了一个敲门板和 在有条件地删除IL-1R1表达或在特定细胞中恢复的小鼠菌株，其中IL-1R1表达 在野生型或IL-1R1缺陷宿主背景中。我们的初步结果表明IL-1R1的表达 在II型肺泡上皮细胞（AECII）上是必要的，足以控制细菌复制， 肺部炎症并防止浪费疾病。 AECII-Intrinsic IL-1R1信号对于抗 - 至关重要 分枝杆菌免疫和预防I型IFN（IFN-I）依赖性中性粒细胞流入。耗尽嗜中性粒细胞或 IFN-I显着降低了细菌载荷，免疫病理学。此外，AECII限制了GM- 肺中的CSF通过减少细菌载荷，重量来保护高度易感的GM-CSF动物 损失和肺病理学。重要的是，IFN-I封锁挽救了I型肺泡（AEC-I）和II型（AECII） 上皮细胞在进行性疾病期间受到损害。根据我们的初步结果，我们 假设在AECII中的IL-1R1信号传导增强了GM-CSF的髓样细胞的抗微生物功能 生产并限制IFN-I产生的病理水平，以维持上皮屏障完整性。我们 有三个特定的目标。在AIM1中，我们将研究GM-CSF在调节抗菌免疫中的作用 通过检查从缺乏或表达的小鼠获得的细菌适应性和复制动力学 IL-1R1在AECII中的表达。在AIM2中，我们将研究AECII衍生的前列腺素E2（PGE2）在 调节IFN-I反应，并导致致病性嗜中性粒细胞涌入以防止组织损伤。最后，在 AIM3，我们将通过执行IFN-I对肺泡上皮细胞修复和再生的影响 感染肺样品中肺上皮细胞的谱系追踪和空间分析。总体而言，完成 这些目的将为IL-1R1介导的保护性免疫提供机械基础，并揭示原则 靶向气道上皮细胞可增强抗菌免疫并限制不可阻滞的肺损伤 在结核病期间引起的，即使在抗生素治疗后，患者也会导致肺功能障碍。