The contribution of eosinophils and the IL-23/IL-17 axis to host responses to Aspergillus

嗜酸性粒细胞和 IL-23/IL-17 轴对宿主对曲霉反应的贡献

• 批准号: 10163121
• 负责人: Stuart Michael Levitz
• 金额: $ 41.88万
• 依托单位: UNIV OF MASSACHUSETTS MED SCH WORCESTER
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-07-11 至 2023-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10163121
• 关键词: Aerosols; Allergic; Allergic Bronchopulmonary Aspergillosis; Antigen Presentation; Antigens; Aspergillosis; Aspergillus; Aspergillus fumigatus; Asthma; Biology; C Type Lectin Receptors; Clinical Trials; Disease; Epithelial; Epithelial Cells; Functional disorder; Genetic; Human; IL17 gene; Immune response; Immunity; Immunocompromised Host; Immunology; Infection; Interleukin-17; Lung; Lung diseases; MHC Class II Genes; Measures; Mediating; Modeling; Morbidity - disease rate; Mus; Natural Immunity; Orphan; Outcome; Pathology; Persons; Phenotype; Play; Production; Retinoic Acid Receptor; Role; Signal Transduction; Source; T cell response; T-Lymphocyte; Testing; adaptive immune response; adaptive immunity; autocrine; cellular targeting; cytokine; dectin 1; eosinophil; experimental study; immunological status; immunopathology; insight; interleukin-23; mortality; mouse dectin-2; mouse model; pathogenic fungus; receptor; response; transcription factor

Project Summary/Abstract The spectrum of diseases caused by the opportunistic fungal pathogen, Aspergillus, depends in large measure upon the immune status of the host. Over 5 million people suffer from allergic forms of aspergillosis including allergic bronchopulmonary aspergillosis and severe asthma with fungal sensitization. Eosinophils are hallmarks and drivers of allergic aspergillosis but the mechanisms by which eosinophils contribute to immunopathology are not well understood. On the other end of the spectrum, invasive aspergillosis occurs mostly in severely immunocompromised persons; over 200,000 people annually are afflicted and the mortality rate is high. The contribution of eosinophils to immunity in invasive aspergillosis is uncertain; however, we have observed that mice lacking eosinophils are hypersusceptible. The IL-23/IL17 axis is postulated to play a role in immune responses to Aspergillus species and to contribute to the pathophysiology of some forms of asthma. We have discovered that following pulmonary challenge with live Aspergillus fumigatus conidia or aerosol challenge of sensitized mice with A. fumigatus antigens, lung eosinophils express IL-23 and IL-17. Moreover, mice lacking eosinophils have reduced IL-23 and IL-17 in their lungs following A. fumigatus challenge. The overarching hypotheses of this proposal are: 1) eosinophils are major drivers of the IL-23/IL-17 axis in pulmonary aspergillosis; and 2) eosinophilic production of IL-23 and IL-17 is protective in invasive aspergillosis but detrimental in allergic aspergillosis. Our interrelated specific aims will test these hypotheses. Aim 1 is to determine the drivers and consequences of eosinophil production of IL-23/IL-17 in allergic and invasive aspergillosis. We hypothesize that eosinophil expression of IL-23 and IL-17, driven by signaling through C-type lectin receptors, informs immunological responses and outcome in IPA and APA. Aim 2 is to assess the contribution of IL-23R and RORγt to the phenotype of IL-17+/IL-23+ lung eosinophils elicited in response to live Aspergillus and Aspergillus antigens. We postulate that in the setting of Aspergillus stimulation, eosinophils respond to autocrine IL-23 via the IL-23R which turns on expression of the transcription factor RORγt leading to IL-17 expression. Aim 3 is to elucidate cellular targets of eosinophil IL-23/IL-17 responsible for innate and adaptive immune responses. Mechanistic insights into how eosinophil IL-23 and IL-17 expression informs innate and adaptive immunity to Aspergillus will be garnered as we test the hypothesis that lung epithelial cells and T cells are cellular targets of eosinophil-derived IL-17 and IL-23, respectively. Successful completion of the proposed hypothesis-driven studies will have a large overall impact on our understanding of eosinophil biology, the IL-23/IL-17 axis, and the immunology of invasive and allergic forms of aspergillosis. The project has translational significance as the results could suggest rationales for clinical trials in humans with diseases featuring eosinophil-mediated pathology.

项目概要/摘要 由机会性真菌病原体曲霉引起的疾病谱在很大程度上取决于 超过 500 万人患有过敏性曲霉病，包括曲霉病。 过敏性支气管肺曲霉病和伴有真菌致敏的严重哮喘是其标志。 和过敏性曲霉病的驱动因素，但嗜酸性粒细胞促进免疫病理学的机制 另一方面，侵袭性曲霉病主要发生在严重的患者中。 免疫功能低下者；每年有超过20万人受到影响，死亡率很高。 嗜酸性粒细胞对侵袭性曲霉病免疫的贡献尚不确定，但我们观察到： 缺乏嗜酸性粒细胞的小鼠高度敏感，推测 IL-23/IL17 轴在免疫中发挥作用。 我们已经了解了对曲霉属物种的反应并有助于某些形式哮喘的病理生理学。 发现用活烟曲霉分生孢子进行肺部攻击或用气溶胶攻击 烟曲霉抗原致敏的小鼠，肺嗜酸性粒细胞表达IL-23和IL-17，此外，缺乏烟曲霉抗原的小鼠肺嗜酸性粒细胞表达IL-23和IL-17。 烟曲霉攻击后，肺部嗜酸性粒细胞 IL-23 和 IL-17 减少。 该提议的假设是：1) 嗜酸性粒细胞是肺中 IL-23/IL-17 轴的主要驱动因素 曲霉病；2) 嗜酸性粒细胞产生 IL-23 和 IL-17 对侵袭性曲霉病具有保护作用，但 我们的相关具体目标将检验这些假设，目标 1 是。 确定过敏性和侵袭性嗜酸性粒细胞产生 IL-23/IL-17 的驱动因素和后果 我们勇敢地发现嗜酸性粒细胞表达 IL-23 和 IL-17，由 C 型信号传导驱动。 目标 2 是评估 IPA 和 APA 的免疫反应和结果。 IL-23R 和 RORγt 对活体反应引起的 IL-17+/IL-23+ 肺嗜酸性粒细胞表型的贡献 我们假设在曲霉菌刺激的情况下，嗜酸性粒细胞。 通过 IL-23R 对自分泌 IL-23 做出反应，IL-23R 打开转录因子 RORγt 的表达 目标 3 是阐明嗜酸性粒细胞 IL-23/IL-17 负责先天性和IL-17 表达的细胞靶点。 适应性免疫反应的机制见解嗜酸性粒细胞 IL-23 和 IL-17 表达如何提供信息 当我们测试肺上皮细胞的假设时，将收集对曲霉菌的先天性和适应性免疫 和 T 细胞分别是嗜酸性粒细胞衍生的 IL-17 和 IL-23 的细胞靶标。 提出的假设驱动的研究将对我们对嗜酸性粒细胞生物学的理解产生巨大的总体影响， IL-23/IL-17 轴，以及侵袭性和过敏性曲霉病的免疫学。 具有转化意义，因为结果可以为人类疾病临床试验提供理论依据 以嗜酸性粒细胞介导的病理学为特征。

项目成果

Dysregulated Pulmonary Inflammatory Responses Exacerbate the Outcome of Secondary Aspergillosis Following Influenza.

肺部炎症反应失调会加剧流感后继发曲霉病的结果。

• 发表时间: 2023-06-30
• 作者: Lee, Chrono K;Oliveira, Lorena V N;Akalin, Ali;Specht, Charles A;Lourenco, Diana;Gomez, Christina L;Ramirez;Wang, Jennifer P;Levitz, Stuart M
• 通讯作者: Levitz, Stuart M