The role of IFNAR2 in regulation of damage during A. fumigatus lung infection

项目摘要 作为一种机会性人类病原体，全球发病率超过300，000例/年， 产率为40- 80%;烟曲霉（A.f.）在免疫系统改变的人的肺部生长 应答最近流感患者感染侵袭性肺曲霉菌病（IPA）的病例表明， 抗流感免疫应答可以产生暂时抑制的肺部免疫环境， A.F.感染已知流感对I型IFN信号的操纵使肺允许继发性 细菌感染，表明I型IFN信号可能调节肺免疫环境。 在这个项目中，申请人试图了解I型IFN信号转导的贡献， 异源二聚体I型IFN受体IFNAR 1和IFNAR 2的单个亚基，以控制损伤 在A. F。感染！具体而言，初步数据表明，缺乏I型IFN受体， （IFNAR）2亚基（Ifnar 2-/-小鼠）导致响应于A.f.感染， 而不存在IFNAR 1（Ifnar 1-/-小鼠）则不存在。此外，在WT或Ifnar 1-/-小鼠中IFNAR 2的存在， 导致早期A.f.与IFNAR 2-/-小鼠相比，IFNAR 2干扰IFNAR 1-/-小鼠的清除率。 介导的A.f.间隙为了解决我们的假设，IFNAR 2，虽然它调节宿主的损害， 反应，也干扰IFNAR 1控制A. f.感染，我们将（1）确定细胞 IFNAR 2调节A.f.感染这将是 （Subaim 1）鉴定参与IFNAR 2介导的细胞凋亡调控的效应细胞。 损伤和真菌清除反应;和（Subaim 2）确定IFNAR 2如何干扰IFNAR 1- 介导的真菌清除。 这项提议的结果将开始首次阐明I型干扰素信号传导的差异 调节A.f.期间宿主的损害反应。感染及其在抗真菌免疫中作用。这些结果 将允许更好地理解I型IFN信号传导的保护机制，这可以指导治疗。 设计新的A.f.免疫疗法在未来 申请人的职业目标是成为真菌免疫学领域的独立科学家， 一个重点是了解参与调节易感性和损害反应的宿主机制 从A.F.感染为了实现这一目标，申请人将开始向独立科学家过渡的过程 通过开始申请终身教职职位在春季2020周期。此外，申请人提出了一个 职业发展计划，这将使她获得更多的经验，真菌免疫学/发病机理，赠款 通过实践经验、正式课程工作和指导来提高写作和领导技能。高度 完成合作者在类似领域的专业建议的研究项目将指导 申请人的职业发展，并提供有关项目的不同方面的专业知识。

Project Summary As an opportunistic human pathogen with a global incidence of over 300,000 cases/year and a mortality rate ranging from 40-80%, Aspergillus fumigatus (A.f.) thrives in the lungs of individuals with altered immune responses. The recent cases of influenza patients acquiring invasive pulmonary aspergillosis (IPA), suggest that anti-influenza immune responses can create a transiently suppressed lung immune environment that enables A.f. infection. Influenza’s manipulation of type I IFN signaling is known to make lungs permissive to secondary bacterial infection, suggesting that type I IFN signaling may regulate lung immune environments. In this project, the applicant seeks to understand the contribution of type I IFN signaling through the individual subunits of the heterodimeric type I IFN receptor, IFNAR1 and IFNAR2, to control of damage responses during A.f. infection.!Specifically, preliminary data demonstrate that absence of the type I IFN receptor (IFNAR) 2 subunit (Ifnar2-/- mice) results in increased lung damage and morbidity in response to A.f. infection, while absence of IFNAR1 (Ifnar1-/- mice) does not. Moreover, presence of IFNAR2 in either WT or Ifnar1-/- mice results in decreased early A.f. clearance compared to Ifnar2-/- mice, suggesting IFNAR2 interferes with IFNAR1- mediated A.f. clearance. To address our hypothesis that IFNAR2, while it regulates the host damage response, also interferes with the ability of IFNAR1 to control A.f. infection, we will (1) determine the cellular mechanism for IFNAR2 regulation of the damage response to and control of A.f. infection. This will be accomplished by: (Subaim 1) Identification of the effector cells involved in IFNAR2-mediated regulation of the damage and fungal clearance response; and (Subaim 2) determining how IFNAR2 interferes with IFNAR1- mediated fungal clearance. The results from this proposal will begin to elucidate for the first time how type I IFN signaling differentially regulates the host damage response during A.f. infection and its role in anti-fungal immunity. Thus, these results will allow for better understanding of the protective mechanisms of type I IFN signaling, which could guide the design of new immune therapies for A.f. in the future. The applicants career goal is to become an independent scientist in the field of fungal immunology with a focus on understanding the host mechanisms involved in regulating susceptibility to and the damage response from A.f. infection. To meet this goal, the applicant will begin the process of transition to an independent scientist by beginning to apply for tenure-track faculty positions in spring 2020 cycle. Further, the applicant proposes a career development plan that will allow her to gain more experience in fungal immunology/pathogenesis, grant writing, and leadership skills through practical experience, formal course work, and mentoring. Highly accomplished collaborators specialized in similar areas as the proposed research project will mentor the applicants career development and provide expertise on different aspects of the project.