FUNGAL PATHOGENESIS OF MODERATE TO SEVERE ASTHMA

中度至重度哮喘的真菌发病机制

基本信息

批准号：
10357580
负责人：
DAVID B CORRY
金额：
$ 50.52万
依托单位：
BAYLOR COLLEGE OF MEDICINE
依托单位国家：
美国
项目类别：
财政年份：
2018
资助国家：
美国
起止时间：
2018-03-23 至 2024-02-29
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10357580
关键词：
Allergic Allergic inflammation Animal Model Antifungal Agents Asthma B-Lymphocytes Binding Biological Assay Blood Coagulation Factor Blood coagulation Cells Chronic Coagulants Coin Data Development Diagnosis Disease Dissection Endogenous Factors Environment Epithelial Cells Fibrinogen Fungal Spores Growth Human ITGAM gene ITGB2 gene Immune Immune System Diseases Immune response Immunity In Vitro Individual Inhalation Innate Immune Response Integrins Link Lower respiratory tract structure Lung Macrophage-1 Antigen Mediating Membrane Molds Molecular Mus Mutation Mycoses Pathogenesis Peptide Hydrolases Peripheral Blood Mononuclear Cell Phenotype Physiological Prevalence Proteins Prothrombin Pulmonary Inflammation Reproduction spores Research Respiratory Mucosa Respiratory Tract Infections Role STAT6 gene Sampling Severities Signal Transduction Sputum T-Lymphocyte TLR4 gene Testing Thrombin Tissue-Specific Gene Expression United States airway epithelium airway hyperresponsiveness allergic airway disease allergic airway inflammation asthma model asthmatic base chronic rhinosinusitis cohort fibrinopeptides gamma fungus human disease immune activation improved macrophage monocyte new therapeutic target novel patient subsets peripheral blood prevent response transcription factor transcriptome transcriptome sequencing

项目摘要

The broad, long-term objective of this proposal is to understand the causes of chronic asthma and thereby improve diagnosis and therapy of this common and debilitating ailment. We showed previously how innate immune activation in response to fungal infection of the airway is linked to the development of T helper 2 (TH2)- biased allergic airway inflammation and associated diseases (asthma and chronic rhinosinusitis). Fungi are ubiquitous in human environments and readily gain access to the airway mucosal membrane through constant inhalation of conidia (spores). We have shown that fungi isolated from the human airway can cause airway hyperreactivity in mice, suggesting that airway fungal growth, i.e., airway mycosis, activates innate and acquired immune responses that could cause asthma in susceptible individuals. This is further supported by our discovery in mice that secreted fungal proteinases cleave fibrinogen in the airways to form cleavage products (FCPs) that activate Toll like receptor 4 (TLR4) to induce fungistatic innate immune responses. However, how these factors mediate allergic inflammation in the lungs remain unknown. Our central hypothesis states that fungal proteinase-mediated cleavage of fibrinogen initiates allergic airway disease and fungistatic innate immune responses in the airways. We will test this hypothesis through the following Aims: 1) Determine the molecular mechanism by which FCPs initiate allergic inflammation and antifungal immunity through TLR4. Hypotheses: Fungal proteinases cleave fibrinogen to yield FCPs that 1) signal through TLR4 via the CD18-CD11b integrin heterodimer (Mac-1) to 2) activate STAT6 and NF-κB. We will use mice with constitutive and targeted deletions of STAT6, NF-κB, and Mac-1 as well as mice harboring a mutation in the fibrinogen gamma chain that prevents binding to Mac-1 to test our hypothesis, confirming our findings using human monocyte derived macrophages. 2) Determine how FCPs initiate allergic inflammation and antifungal immunity through airway epithelia of asthmatics. Hypotheses: 1) Epithelial cells secrete coagulant factors in response to fungal proteinases 2) FCPs initiate allergic and anti-fungal responses mediated by enhanced secretion of airway coagulant factors by airway epithelial cells. We will determine the physiological significance of FCP-mediated induction of clotting factors (e.g., fibrinogen, prothrombin) regarding antifungal immunity and chronic allergic inflammation using animal models of asthma and human airway epithelial cells. 3) Determine the mechanism of innate antifungal immune dysfunction in asthmatics with airway mycosis. Hypothesis: Immune cells from a subset of patients with moderate to severe asthma and airway mycosis are unable to restrain fungal growth in vitro. We will examine the fungistatic ability of human monocyte-derived macrophages (HMDM) against fungal conidia. To resolve the signatures of effective and ineffective innate immune responses to fungi in asthmatics, we will study extreme phenotypes, performing differential transcriptome analyses of HMDM in response to fungal conidia by RNA sequencing.

该提案的广泛、长期目标是了解慢性哮喘的原因，从而改善这种常见的、使人衰弱的疾病的诊断和治疗，我们之前已经展示了它是如何与生俱来的。针对气道真菌感染的免疫激活与 T 辅助细胞 2 (TH2) 的发育有关 - 偏向过敏性气道炎症和相关疾病（哮喘和慢性鼻窦炎）。在人类环境中普遍存在，并且通过持续的接触很容易进入气道粘膜吸入分生孢子（孢子）我们已经证明，从人体呼吸道分离出的真菌会引起呼吸道感染。小鼠的高反应性，表明气道真菌生长，即气道真菌病，激活了先天和获得性免疫反应可能导致易感人群出现哮喘，这一点得到了进一步的支持。我们在分泌真菌蛋白酶的小鼠中发现，它们会裂解气道中的纤维蛋白原以形成裂解激活 Toll 样受体 4 (TLR4) 以诱导抑制真菌先天免疫反应的产品 (FCP)。然而，这些因素如何介导肺部过敏性炎症仍不清楚。假设指出真菌蛋白酶介导的纤维蛋白原裂解引发过敏性气道疾病气道中抑制真菌的先天免疫反应我们将通过以下目的检验这一假设：1) 确定 FCP 引发过敏性炎症和抗真菌免疫的分子机制假设：真菌蛋白酶裂解纤维蛋白原产生 FCP，1) 通过 TLR4 发出信号。 CD18-CD11b 整合素异二聚体 (Mac-1) 至 2) 激活 STAT6 和 NF-κB 我们将使用小鼠。 STAT6、NF-κB 和 Mac-1 的组成型和靶向缺失以及具有 STAT6、NF-κB 和 Mac-1 突变的小鼠纤维蛋白原伽马链阻止与 Mac-1 结合来检验我们的假设，并使用人单核细胞衍生的巨噬细胞 2) 确定 FCP 如何引发过敏性炎症和抗真菌。哮喘患者通过气道上皮细胞进行免疫假设：1）上皮细胞分泌凝血因子。对真菌蛋白酶的反应 2) FCP 启动由增强介导的过敏和抗真菌反应我们将确定气道上皮细胞分泌气道凝血因子的生理意义。 FCP介导的凝血因子（例如纤维蛋白原、凝血酶原）的诱导与抗真菌免疫有关使用哮喘动物模型和人类气道上皮细胞来确定慢性过敏性炎症。气道真菌病哮喘患者先天抗真菌免疫功能障碍的机制假说：来自中度至重度哮喘和气道真菌病患者的免疫细胞无法我们将检查人单核细胞来源的巨噬细胞的抑制真菌能力。 (HMDM) 针对真菌分生孢子来解决有效和无效先天免疫的特征。哮喘患者对真菌的反应，我们将研究极端表型，进行差异转录组通过 RNA 测序分析 HMDM 对真菌分生孢子的反应。

项目成果

期刊论文数量（9）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Acute invasive fungal sinusitis: Epidemiology and outcomes in the United States.

急性侵袭性真菌性鼻窦炎：美国的流行病学和结果。

DOI：
发表时间：
2022
期刊：
影响因子：
0
作者：
Shintani;Luong, Amber U;Ramakrishnan, Vijay R;Tan, Bruce K;French, Dustin D;Kern, Robert C
通讯作者：
Kern, Robert C

Mechanisms of allergy and adult asthma.

过敏和成人哮喘的机制。

DOI：
10.1097/aci.0000000000000601
发表时间：
2020-02-01
期刊：
Current Opinion in Allergy and Clinical Immunology
影响因子：
2.8
作者：
Xuesong Chen;D. Corry;Evan Li
通讯作者：
Evan Li

STAT6 Blockade Abrogates Aspergillus-Induced Eosinophilic Chronic Rhinosinusitis and Asthma, A Model of Unified Airway Disease.

STAT6 阻断可消除曲霉引起的嗜酸粒细胞性慢性鼻窦炎和哮喘（一种统一气道疾病模型）。

DOI：
发表时间：
2022
期刊：
影响因子：
0
作者：
Sun, Hua;Damania, Ashish;Mair, Megan L;Otukoya, Eniola;Li, Yi;Polsky, Katherine;Zeng, Yuying;Alt, Jeremiah A;Citardi, Martin J;Corry, David B;Luong, Amber U;Knight, John Morgan
通讯作者：
Knight, John Morgan

Revisiting the controversy: The role of fungi in chronic rhinosinusitis.

重新审视争议：真菌在慢性鼻窦炎中的作用。

DOI：
发表时间：
2021
期刊：
影响因子：
0
作者：
Tyler, Matthew A;Lam, Kent;Marino, Michael J;Yao, William C;Schmale, Isaac;Citardi, Martin J;Luong, Amber U
通讯作者：
Luong, Amber U

Leukotriene enhanced allergic lung inflammation through induction of chemokine production.

白三烯通过诱导趋化因子的产生增强过敏性肺部炎症。