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

项目摘要 作为一种机会性的人类病原体，全球发病率超过30万例/年，死亡率 烟曲霉Aspergillusfumigatus(A.F.)在免疫功能改变的个体的肺中茁壮成长 回应。最近流感患者感染侵袭性肺曲霉菌病的病例表明 抗流感免疫反应可以创造一个短暂抑制的肺部免疫环境，从而使 A.F.感染。已知流感对I型干扰素信号的操纵使肺部允许继发性 细菌感染，提示I型干扰素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型干扰素信号通过 异源二聚体I型干扰素受体的单个亚基，IFNAR1和IFNAR2，以控制损伤 A.F.期间的响应。具体地说，初步数据表明不存在I型干扰素受体 (IFNAR)2亚单位(Ifnar2-/-小鼠)导致A.F.感染， 而缺乏IFNAR1(Ifnar1-/-小鼠)则不能。此外，在WT或Ifnar1-/-小鼠中存在IFNAR2 结果早期房颤减少。清除与Ifnar2-/-小鼠的比较，提示IFNAR2干扰IFNAR1- 经调解的A.F.通行证。为了解释我们的假设，IFNAR2在调节寄主损害的同时， 也干扰了IFNAR1控制A.F.的能力。感染，我们将(1)确定细胞 IFNAR2对A.F.的危害反应和控制的调节机制感染。这将是 完成：(Subaim 1)鉴定参与IFNAR2介导的调控的效应细胞 损伤和真菌清除反应；以及(Subaim 2)确定IFNAR2如何干扰IFNAR1- 经调节的真菌清除。 这项研究的结果将首次阐明I型干扰素信号的不同。 调节A.F.期间的寄主损伤反应。感染及其在抗真菌免疫中的作用。因此，这些结果 将有助于更好地理解I型干扰素信号的保护机制，这可能指导 为A.F.设计新的免疫疗法。在未来。 申请者的职业目标是成为真菌免疫学领域的一名独立科学家 重点了解与调节易感性和损伤反应有关的宿主机制 来自A.F.感染。为了达到这一目标，申请者将开始向独立科学家过渡的过程 从2020年春季开始申请终身教职。此外，申请人提出了一项 职业发展计划，这将使她在真菌免疫学/发病机制方面获得更多经验， 写作，以及通过实践经验、正规课程工作和指导获得的领导技能。高度 与建议的研究项目类似领域的有成就的合作者将指导 申请者的职业发展，并提供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.