Decoding the mechanism of protective and pathological functions of IL-1 during Tuberculosis

解读IL-1在结核病中的保护和病理功能机制

• 批准号: 10246584
• 负责人: Bibhuti Bhusan Mishra
• 金额: $ 48.7万
• 依托单位: ALBANY MEDICAL COLLEGE
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-09-03 至 2023-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10246584
• 关键词: Anti-Bacterial Agents; Antibiotic Therapy; Antibiotics; Arachidonate 15-Lipoxygenase; Area; Attention; Bacteria; Binding; Bone Marrow; Bone Marrow Cells; Cell surface; Cells; Chimera organism; Chronic; Chronic Disease; Clinic; Communicable Diseases; Complex; Cytokine Signaling; Data; Development; Dinoprostone; Disease; Drug resistance in tuberculosis; Eicosanoid Modulation; Eicosanoids; Endothelial Cells; Endothelium; Epithelial Cells; Failure; Family; Future; Genetic Polymorphism; Genotype; Genus Mycobacterium; Goals; Growth; Hematopoietic; Host Defense; Human; Immune response; Immunity; Impairment; Infection; Inflammation; Inflammatory; Interleukin-1; Interleukin-1 Receptors; Interleukins; Knock-in Mouse; Knockout Mice; Knowledge; Lung; Mediating; Mediator of activation protein; Medical; Microbiology; Modeling; Morbidity - disease rate; Mouse Strains; Multi-Drug Resistance; Mus; Mutant Strains Mice; Mycobacterium tuberculosis; Myeloid Cells; Neutrophilic Infiltrate; Organ; Pathogenesis; Pathogenicity; Pathologic; Pathology; Pathway interactions; Patients; Phagocytes; Pharmacology; Play; Prevalence; Preventive Intervention; Production; Public Health; Pulmonary Tuberculosis; Radiation Tolerance; Receptor Signaling; Regulation; Research; Respiratory Failure; Respiratory physiology; Risk; Role; Signal Pathway; Signal Transduction; Testing; Text; Therapeutic; Therapeutic Intervention; Tissues; Tuberculosis; Virulent; WFDC2 gene; Work; airway epithelium; antimicrobial; base; cell type; chemotherapy; clinically relevant; conditional knockout; congenic; cytokine; design; experimental study; human disease; inhibitor/antagonist; insight; loss of function; macrophage; member; microbicide; microorganism; mortality; mouse model; mycobacterial; neutrophil; novel; pathogen; pathogenic bacteria; promoter; radioresistant; reconstitution; response; restoration; safe patient; selective expression; tuberculosis drugs; tuberculosis immunity; tuberculosis treatment

PROJECT SUMMARY/ABSTRACT Active tuberculosis (TB) is characterized by the failure of the host to control bacterial replication and pathological inflammation in lungs and other organs. Although antibiotics achieve microbiological cure of this disease, inflammation persists even after chemotherapy and is associated with impaired lung functions. Recent studies in humans have shown that genetic polymorphisms in interleukin-1b (a prototypical IL-1 cytokine) promoter increases the risk of hyperinflammation, and long-term respiratory failure during pulmonary TB. Our preliminary data in mice reaffirmed this association as interleukin-1 (IL-1) blockade ameliorates exacerbating inflammation in mouse strains susceptible to TB. IL-1 inhibition therapy is routinely used in the clinic to treat a number of human diseases where this cytokine acts as a pathogenic mediator. But, the role of IL-1 in TB is very complex, as expression of this cytokine is pivotal for host defense early during infection. Mice deficient in this cytokine signaling rapidly succumb to inflammatory TB disease and loss of function genetic polymorphisms in human IL-1R1 were associated with increased risk for active TB. Given these protective functions of IL-1 in TB, drugs that act by antagonizing IL-1 signaling may not be very safe for patients dwelling in TB endemic areas as they elevate the risk for reactivating latent TB. This dichotomous function of IL-1 has not received due attention partly because the pathological functions of this cytokine during TB was perceived as a consequence of failed antimicrobial function in conditions where the host makes sub-optimal level of IL-1. Despite being a well-studied cytokine in terms of its regulation and signaling pathways, the role of different cells in IL-1- mediated protective immunity and pathological inflammation is not explored in details, especially in the context of chronic TB. To bridge this knowledge gap, and with the long-term goal to understand the cell-specific role of IL-1 in TB immunity, we generated conditional deletion and gain-in function mutant mouse strains and discovered that IL-1 provides protection against TB by acting on non-hematopoietic cells, e.g. airway epithelial cells (AECs) and endothelial cells (ECs) that control neutrophil influx, tissue damage and bacterial growth in the lungs. We hypothesize that IL-1 activation on ECs and AECs are integral to protection against chronic TB as it restrains tissue-damaging inflammation caused by uncontrolled neutrophil influx, and boosts anti-microbial immunity. We will test this hypothesis by two specific aims. In aim.1, we will investigate the mechanisms by which AECs and ECs regulate inflammation and microbicidal functions of phagocytes. We will specifically test the contribution of prostaglandin E2/EP4 signaling pathway in mice that express or lack IL-1 receptor on these cells. In aim.2, we will investigate the mechanisms by which neutrophils cause tissue damage in the absence of regulatory signals from AECs and ECs. We will test the hypothesis that neutrophils produce 5- and 12/15- lipoxygenases to generate potent chemo attractants of these cells and amplify inflammation by a feed-forward mechanism. Collectively, these studies will provide an in-depth understanding of the IL-1-mediated immune response involved in protection and pathology, and will lay the groundwork for the future development of cell- specific modulation of IL-1R1-signaling as host-directed therapeutics. Successful completion of the studies proposed here, in our opinion, will provide rationale targeting of various downstream pathways, for which clinically relevant pharmacological inhibitors are available.

项目总结/摘要 活动性结核病（TB）的特征是宿主无法控制细菌复制， 肺部和其他器官的病理性炎症。虽然抗生素可以达到微生物治愈这一点， 在这种疾病中，炎症甚至在化疗后仍然存在，并与肺功能受损有关。最近 对人类的研究表明，白细胞介素-1b（一种原型IL-1细胞因子）的遗传多态性 促进剂增加了肺结核期间炎症过度和长期呼吸衰竭的风险。我们 小鼠的初步数据证实了这种关联，因为白细胞介素-1（IL-1）阻断可改善 对结核病易感的小鼠品系的炎症。IL-1抑制疗法在临床上常规用于治疗 许多人类疾病中，这种细胞因子作为致病介质。但是，IL-1在结核病中的作用是 这是非常复杂的，因为这种细胞因子的表达对于感染早期的宿主防御是关键的。缺陷的小鼠 这种细胞因子信号迅速屈服于炎性结核病和功能丧失遗传多态性 IL-1 R1与活动性TB风险增加相关。考虑到IL-1的这些保护功能， 通过拮抗IL-1信号传导而起作用的药物对结核病流行区的患者可能不是很安全 因为它们增加了重新激活潜伏结核病的风险。IL-1的这种二分功能尚未得到应有的重视。 引起注意的部分原因是，这种细胞因子在结核病期间的病理功能被认为是结核病的后果。 在宿主产生次优水平的IL-1的条件下，尽管是一个 在调节和信号传导途径方面，IL-1和IL-2的不同细胞在IL-1和IL-2中的作用是一种研究得很好的细胞因子。 介导的保护性免疫和病理性炎症没有详细探讨，特别是在上下文中， 慢性肺结核为了弥合这一知识差距，并与长期目标，以了解细胞的具体作用， IL-1在TB免疫中的作用，我们产生了条件性缺失和获得功能突变小鼠品系， 发现IL-1通过作用于非造血细胞，例如气道上皮细胞，提供针对TB的保护 细胞（AEC）和内皮细胞（EC），控制中性粒细胞流入，组织损伤和细菌生长， 肺我们假设内皮细胞和肺动脉内皮细胞上的IL-1活化是预防慢性结核病的必要条件 因为它抑制了由不受控制的中性粒细胞流入引起的组织损伤性炎症， 免疫力我们将通过两个具体目标来检验这一假设。在目标1中，我们将通过以下方式研究其机制： 其中AEC和EC调节吞噬细胞的炎症和杀微生物功能。我们将专门测试 前列腺素E2/EP 4信号通路在表达或缺乏IL-1受体小鼠中的作用 细胞在目的2中，我们将研究中性粒细胞引起组织损伤的机制， 来自AEC和EC的调节信号。我们将检验中性粒细胞产生5-和12/15- 脂氧合酶产生这些细胞的有效化学引诱剂，并通过前馈放大炎症 机制总的来说，这些研究将提供对IL-1介导的免疫调节的深入理解。 反应参与保护和病理，并将奠定基础，为未来的发展细胞， 特异性调节IL-1 R1信号传导作为宿主导向的治疗剂。顺利完成学业 在我们看来，这里提出的将提供针对各种下游途径的合理性， 临床上相关的药理学抑制剂是可获得的。