INITIATION OF THE IMMUNE RESPONSE TO ASPERGILLUS FUMIGATUS

对烟曲霉的免疫反应的启动

基本信息

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
项目类别：
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

项目摘要

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.

项目概要侵袭性曲霉病是一种毁灭性的真菌感染，也是全世界最常见的霉菌肺炎，每年估计有 200,000 起案件。烟曲霉（Aspergillus fumigatus），最常见的侵袭性病原体曲霉病，形成人类每天吸入的无处不在的空气传播孢子。在免疫能力强的情况下个体的呼吸道先天免疫系统可以防止组织侵入性菌丝的形成，这是一个关键的因素免疫检查点。血液系统恶性肿瘤患者、骨髓和肺移植患者接受者，以及最近在重症监护病房的 COVID-19 患者中，先天的数字或功能缺陷免疫功能低下导致侵袭性疾病。尽管有现代抗真菌药物，死亡率仍保持在 20- 40% 属于高危人群，强调需要加深对分子和细胞基础的了解消除免疫力以推进基于免疫的辅助方法。在第二个资助期，我们利用真菌生物报告仪报告细胞死亡模式来发现中性粒细胞和单核细胞衍生的树突状细胞在被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节的细胞死亡机制的概念是新颖的对于烟曲霉来说，取决于宿主 NADPH 氧化酶的活性。 NADPH氧化酶依赖性真菌杀伤是由两个新颖的、重要的细胞间串扰电路调节的，该电路涉及早期产生 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。在目标 1，我们确定 GM-CSF 的重要细胞来源，并根据初步数据，重点关注肺部内皮和上皮细胞作为中性粒细胞依赖性真菌杀伤的调节剂。在目标 2 中，我们定义 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，以及通过戊糖磷酸测试其在 NAPDH 氧化酶组装、激活和中性粒细胞代谢中的作用途径及其与 GM-CSF 回路的协同作用以介导灭菌免疫。拟议的研究具有重要意义和创新性，因为它们整合了肺之间的先天免疫串扰内皮、上皮和 pDC 区室以及感染的骨髓吞噬细胞形成综合模型抵抗霉菌病原体的呼吸道免疫力。了解的诱导、调节和参与者先天免疫串扰解决了一个关键的知识差距，将为免疫增强策略提供信息弱势患者群体。