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.

项目总结/摘要 由条件致病真菌曲霉菌引起的疾病谱在很大程度上取决于 宿主的免疫状态。超过500万人患有过敏性曲菌病， 过敏性支气管肺曲霉病和严重哮喘伴真菌致敏。嗜酸性粒细胞是 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 并没有得到很好的理解。另一方面，侵袭性曲霉病大多发生在严重的 免疫力低下的人;每年有20多万人患病，死亡率很高。的 嗜酸性粒细胞在侵袭性曲霉病中对免疫的作用尚不确定;然而，我们观察到， 缺乏嗜酸性粒细胞的小鼠是过敏的。IL-23/IL 17轴被假定在免疫调节中起作用。 对曲霉属物种的反应，并有助于某些形式的哮喘的病理生理学。我们有 发现在用活的烟曲霉分生孢子进行肺部攻击或用烟曲霉的气溶胶攻击后， 致敏小鼠A.肺嗜酸性粒细胞表达IL-23和IL-17。此外，缺乏 嗜酸性粒细胞在A.烟曲霉菌攻毒。总体 该建议的假设是：1）嗜酸性粒细胞是肺内IL-23/IL-17轴的主要驱动因素， 嗜酸性粒细胞产生IL-23和IL-17在侵袭性曲霉病中具有保护作用， 对过敏性曲霉病有害。我们相互关联的具体目标将检验这些假设。目标1是 确定过敏性和侵袭性疾病中嗜酸性粒细胞产生IL-23/IL-17的驱动因素和后果， 曲霉病我们假设嗜酸性粒细胞表达IL-23和IL-17，由通过C-型胶原的信号传导驱动， 凝集素受体，告知IPA和阿帕的免疫应答和结果。目标2是评估 IL-23 R和RORγt对IL-17+/IL-23+肺嗜酸性粒细胞表型的贡献 曲霉属和曲霉属抗原。我们推测，在曲霉菌刺激的情况下，嗜酸性粒细胞 通过IL-23 R应答自分泌IL-23，IL-23 R开启转录因子RORγt的表达， IL-17的表达。目的3是阐明嗜酸性粒细胞IL-23/IL-17的细胞靶点， 适应性免疫反应嗜酸性粒细胞IL-23和IL-17表达如何影响 当我们检验肺上皮细胞 T细胞分别是嗜酸性粒细胞衍生的IL-17和IL-23的细胞靶。成功完成 所提出的假设驱动的研究将对我们理解嗜酸性粒细胞生物学具有很大的总体影响， IL-23/IL-17轴，以及侵袭性和过敏性曲菌病的免疫学。该项目 翻译意义，因为结果可能为人类疾病的临床试验提供依据。 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。

• 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