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.

项目摘要/摘要 由机会性真菌病原体曲霉引起的疾病范围取决于大量测量 在宿主的免疫状态下。超过500万人患有过敏反应的曲霉病 过敏性支气管肺曲霉病和严重的哮喘具有真菌敏感性。嗜酸性粒细胞是标志 和过敏性曲霉病的驱动因素，但嗜酸性粒细胞有助于免疫病理学的机制 不太了解。在频谱的另一端，侵袭性曲霉病主要发生在严重的 免疫功能低下的人；每年超过200,000人受到折磨，死亡率很高。这 嗜酸性粒细胞在浸润性曲霉病中的免疫力的贡献尚不确定。但是，我们观察到 缺乏嗜酸性粒细胞的小鼠可以过敏。 IL-23/IL17轴张贴以在免疫中发挥作用 对曲霉物种的反应，并为某些形式的哮喘的病理生理做出贡献。我们有 发现在实时曲霉挑战曲曲霉的挑战之后 用烟曲霉抗原敏化小鼠，肺嗜酸性粒子表达IL-23和IL-17。而且，老鼠缺乏 在烟曲霉挑战之后，嗜酸性粒细胞在其肺中降低了IL-23和IL-17。总体 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）IL-23和IL-17的嗜酸性粒细胞产生在浸润性曲霉病中受到保护，但 过敏性曲霉病有害。我们相互关联的特定目标将检验这些假设。目标1是 确定IL-23/IL-17在过敏性和侵入性中的嗜酸性粒细胞产生的驱动因素和后果 曲霉病。我们假设通过信号通过C型驱动的IL-23和IL-17的嗜酸性粒细胞表达 凝集素受体，告知IPA和APA中的免疫反应和结果。目标2是评估 IL-23R和RORγT对IL-17+/IL-23+肺嗜酸性粒细胞的表型的贡献 曲霉和曲霉抗原。我们假设在曲霉刺激的情况下，嗜酸性粒细胞 通过IL-23R响应自分泌IL-23，该IL-23R打开转录因子RORγT领先的表达 至IL-17表达。目标3是阐明嗜酸性粒细胞IL-23/IL-17的细胞靶标，负责先天和 自适应免疫调查。关于嗜酸性粒细胞IL-23和IL-17表达信息的机理见解 当我们测试肺上皮细胞的假设时，将获得对曲霉的先天和适应性免疫学。 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。成功完成 拟议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很大的影响， IL-23/IL-17轴以及曲霉病的侵入性和过敏性形式的免疫学。该项目有 翻译意义，因为结果可能表明疾病人类临床试验的理由 具有嗜酸性粒细胞介导的病理学。

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。

• DOI: 10.1101/2023.06.27.546808
• 发表时间: 2023
• 期刊: bioRxiv : the preprint server for biology
• 作者: Lee,ChronoK;Oliveira,LorenaVN;Akalin,Ali;Specht,CharlesA;Lourenco,Diana;Gomez,ChristinaL;Ramirez-Ortiz,ZaidaG;Wang,JenniferP;Levitz,StuartM
• 通讯作者: Levitz,StuartM