INITIATION OF THE IMMUNE RESPONSE TO ASPERGILLUS FUMIGATUS

对烟曲霉的免疫反应的启动

• 批准号: 10449393
• 负责人: TOBIAS M HOHL
• 金额: $ 67.85万
• 依托单位: SLOAN-KETTERING INST CAN RESEARCH
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-06-06 至 2026-06-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10449393
• 关键词: Address; Amplifiers; Antifungal Agents; Aspergillosis; Aspergillus; Aspergillus fumigatus; Binding; Bone Marrow Transplantation; COVID-19 patient; CXC Chemokines; CXCL10 gene; Cell Death; Cell Death Process; Cells; Data; Defect; Dendritic Cells; Disease; Elements; Endothelial Cells; Endothelium; Epithelial; Epithelial Cells; Etiology; Eukaryota; Fright; Funding; Goals; Granulocyte-Macrophage Colony-Stimulating Factor; Hematologic Neoplasms; Host Defense; Human; Hyphae; Immune; Immune response; Immune system; Immunity; Immunocompetent; Immunocompromised Host; Individual; Infection; Inhalation; Innate Immune System; Intensive Care Units; Interferons; Interleukin-1 Receptors; Knowledge; Lead; Ligands; Lung; Lung Transplantation; Mediating; Mediator of activation protein; Metabolism; Modeling; Molds; Molecular; Molecular Target; Mucous Membrane; Mycoses; Myelogenous; Myeloid Cells; NADPH Oxidase; Natural Immunity; Outcome; Oxidases; Participant; Patients; Pentosephosphate Pathway; Phagocytes; Pilot Projects; Pneumonia; Production; Property; Proteomics; Receptor Signaling; Regulation; Reporting; Reproduction spores; Role; Shapes; Signal Transduction; Source; System; Testing; Therapeutic; Tissues; Transplant Recipients; Work; base; cellular targeting; chemokine receptor; cytokine; experimental study; fungus; high risk population; immune checkpoint; immune function; improved; inflammatory milieu; innate immune function; innovation; interleukin-23; monocyte; mortality; neutrophil; novel; novel strategies; pathogen; pathogenic fungus; prevent; receptor; recruit; respiratory; transcriptomics

PROJECT SUMMARY Invasive aspergillosis is devastating fungal infection and the most common form of mold pneumonia worldwide, with an estimated 200,000 cases annually. Aspergillus fumigatus, the most common etiologic agent of invasive aspergillosis, forms ubiquitous airborne spores that humans inhaled on daily basis. In immune competent individuals the respiratory innate immune system prevents the formation of tissue-invasive hyphae, a critical immunologic checkpoint. In patients with hematologic malignancies, in bone marrow and lung transplant recipients, and recently, in intensive care unit patients with COVID-19, numeric or functional defects in innate immune function lead to invasive disease. Despite contemporary antifungal drugs, mortality rates remain at 20- 40% in high risk groups, underscoring the need for improved understanding of the molecular and cellular basis of sterilizing immunity to advance immune-based adjunctive approaches. In the second funding period, we harnessed a fungal bioreporter that reports the mode of cell death to discover that neutrophils and monocyte-derived dendritic cells induce a regulated cell death in engulfed fungal cells. The concept that a higher eukaryote can exploit a regulated cell death machinery in a lower eukaryote is novel and, in the case of A. fumigatus, depends on host NADPH oxidase activity. NADPH oxidase-dependent fungal killing is modulated by two novel, essential intercellular crosstalk circuits that involves the early production of GM-CSF (GM-CSF circuit) and plasmacytoid dendritic cells (pDC circuit). During the next project period, we propose to gain a deeper understanding of the GM-CSF and pDC circuits. In Aim 1, we identify the essential cellular source of GM-CSF and, based on preliminary data, focus on pulmonary endothelial and epithelial cells as regulators of neutrophil-dependent fungal killing. In Aim 2, we define the pDC circuit and candidate transmitters and test models of direct or indirect activation by fungal cells or the lung inflammatory milieu. In Aim 3, we define the mechanisms by which the pDC circuit regulates neutrophils, and test its role in NAPDH oxidase assembly, activation, and neutrophil metabolism via the pentose phosphate pathway and its cooperativity with the GM-CSF circuit to mediate sterilizing immunity. The proposed studies are significant and innovative because they integrate innate immune crosstalk between the pulmonary endothelial, epithelial, and pDC compartments and infected myeloid phagocytes into a comprehensive model of respiratory immunity against mold pathogens. Understanding the induction, regulation, and participants of innate immune crosstalk addresses a critical knowledge gap that will inform immune-enhancing strategies in vulnerable patient groups.

项目摘要 侵袭性曲霉病是一种毁灭性的真菌感染，也是世界范围内最常见的霉菌性肺炎， 估计每年有20万例。烟曲霉，最常见的病原体的侵袭性 曲霉菌病，形成无处不在的空气传播的孢子，人类每天吸入。免疫功能正常 个体的呼吸先天免疫系统阻止组织侵入性菌丝的形成，这是一个关键的 免疫检查点在恶性血液病患者中，在骨髓和肺移植中 最近，在重症监护病房的COVID-19患者中，先天性心脏病的数量或功能缺陷 免疫功能导致侵袭性疾病。尽管有现代抗真菌药物，死亡率仍保持在20- 40%在高危人群中，强调需要提高对分子和细胞基础的理解 消灭免疫力来推进基于免疫的预防方法。 在第二个资助期，我们利用了一种真菌生物报告器，它报告细胞死亡的模式， 嗜中性粒细胞和单核细胞衍生的树突状细胞在吞噬的真菌细胞中诱导受调节的细胞死亡。 高等真核生物可以利用低等真核生物中受调控的细胞死亡机制的概念是新颖的 在A.烟曲霉的生长依赖于宿主NADPH氧化酶的活性。NADPH氧化酶依赖性真菌 杀伤是由两个新的，重要的细胞间串扰电路，涉及早期生产的 GM-CSF（GM-CSF回路）和浆细胞样树突状细胞（pDC回路）。 在下一个项目期间，我们建议更深入地了解GM-CSF和pDC电路。在 目的1，我们确定了GM-CSF的基本细胞来源，并在初步资料的基础上， 内皮细胞和上皮细胞作为中性粒细胞依赖性真菌杀伤的调节因子。在目标2中，我们定义了pDC 电路和候选发射器以及真菌细胞或肺直接或间接激活的测试模型 炎症环境在目标3中，我们定义了pDC回路调节中性粒细胞的机制， 测试其在NAPDH氧化酶组装、活化和中性粒细胞通过磷酸戊糖代谢中的作用 途径及其与GM-CSF回路的协同性介导杀菌免疫。拟议的研究 是重要的和创新的，因为它们整合了肺部和肺部之间的先天免疫串扰， 内皮、上皮和pDC区室和感染的髓样吞噬细胞整合到一个综合模型中 对霉菌病原体的呼吸免疫力。了解的诱导，规则，和参与者 先天免疫串扰解决了一个关键的知识缺口，这将为免疫增强策略提供信息， 弱势患者群体。