FUNGAL PATHOGENESIS OF MODERATE TO SEVERE ASTHMA

中度至重度哮喘的真菌发病机制

• 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
• 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

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.

这项提案的广泛、长期目标是了解慢性哮喘的原因，从而 改善对这种常见的使人衰弱的疾病的诊断和治疗。我们之前展示了 呼吸道真菌感染后的免疫激活与辅助性T细胞2（TH 2）的产生有关。 偏过敏性气道炎症和相关疾病（哮喘和慢性鼻窦炎）。真菌是 在人类环境中普遍存在，并且容易通过恒定的呼吸通道进入气道粘膜。 吸入分生孢子（孢子）。我们已经证明，从人体呼吸道分离的真菌可以引起呼吸道 高反应性，表明气道真菌生长，即，气道真菌病，激活先天性和 获得性免疫反应可能导致易感个体哮喘。进一步支持了这一点 我们在小鼠中发现，分泌的真菌蛋白酶切割气道中的纤维蛋白原， 在一些实施方案中，本发明涉及活化Toll样受体4（TLR 4）以诱导抑真菌先天免疫应答的FCPs。 然而，这些因素如何介导肺部的过敏性炎症仍然未知。我们的中央 一种假说认为真菌蛋白酶介导的纤维蛋白原裂解引发过敏性气道疾病， 抑制真菌的先天免疫反应。我们将通过以下目的来检验这一假设：1） 确定FCPs引发过敏性炎症和抗真菌免疫的分子机制 通过TLR 4。假设：真菌蛋白酶切割纤维蛋白原以产生FCP，其1）通过TLR 4经由 CD 18-CD 11 B整联蛋白异二聚体（Mac-1）2）激活STAT 6和NF-κB。我们会用老鼠 STAT 6、NF-κB和Mac-1的组成性和靶向缺失以及在STAT 6、NF-κB和Mac-1中携带突变的小鼠。 纤维蛋白原γ链，阻止结合Mac-1来测试我们的假设，证实我们的研究结果，使用 人单核细胞衍生的巨噬细胞。2)确定FCPs如何引发过敏性炎症和抗真菌药物 通过气道上皮细胞免疫。假设：1）上皮细胞分泌凝血因子， 2）FCPs启动过敏和抗真菌反应， 气道上皮细胞分泌气道凝血因子。我们将确定其生理意义 FCP介导的凝血因子诱导（例如，纤维蛋白原、凝血酶原）， 使用哮喘动物模型和人气道上皮细胞的慢性过敏性炎症。3)确定 支气管哮喘合并气道真菌感染时天然抗真菌免疫功能紊乱的机制假设： 来自中重度哮喘和气道真菌病患者亚群的免疫细胞不能 在体外抑制真菌生长。我们将研究人类单核细胞衍生的巨噬细胞的抑真菌能力 （HMDM）对真菌分生孢子的抗性。为了解决有效和无效的先天免疫的特征， 哮喘患者对真菌的反应，我们将研究极端的表型， 通过RNA测序分析HMDM对真菌分生孢子的反应。

项目成果

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

• DOI: 10.3389/fimmu.2022.818017
• 发表时间: 2022
• 期刊: Frontiers in immunology
• 影响因子: 7.3
• 作者: Sun H;Damania A;Mair ML;Otukoya E;Li YD;Polsky K;Zeng Y;Alt JA;Citardi MJ;Corry DB;Luong AU;Knight JM
• 通讯作者: Knight JM

Airway Mycosis and the Regulation of Type 2 Immunity.

气道真菌病和 2 型免疫的调节。

• DOI: 10.3390/jof6020074
• 发表时间: 2020
• 期刊: Journal of fungi (Basel, Switzerland)
• 作者: Knight,JohnMorgan;Wu,Yifan;Mauk,Kelsey;Weatherhead,Jill;Anvari,Sara;Kheradmand,Farrah;Corry,DavidB
• 通讯作者: Corry,DavidB

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

• DOI: 10.1002/alr.22826
• 发表时间: 2021-11
• 期刊: International forum of allergy & rhinology
• 影响因子: 6.4
• 作者: Tyler MA;Lam K;Marino MJ;Yao WC;Schmale I;Citardi MJ;Luong AU
• 通讯作者: Luong AU

Reduced pro-inflammatory dendritic cell phenotypes are a potential indicator of successful peanut oral immunotherapy.

• DOI: 10.1371/journal.pone.0264674
• 发表时间: 2022
• 期刊: PLOS ONE
• 影响因子: 3.7
• 作者: Anvari, Sara;Watkin, Levi B.;Minard, Charles G.;Schuster, Kimberly;Hassan, Oluwatomi;Anagnostou, Aikaterini;Orange, Jordan S.;Corry, David B.;Davis, Carla M.
• 通讯作者: Davis, Carla M.

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。

• DOI: 10.1007/s10238-014-0292-7
• 发表时间: 2015
• 期刊: Clinical and experimental medicine
• 影响因子: 4.6
• 作者: Shin,Kihyuk;Hwang,JungJoo;Kwon,Bo-In;Kheradmand,Farrah;Corry,DavidB;Lee,Seung-Hyo
• 通讯作者: Lee,Seung-Hyo