Friday, April 18, 2025
4/18/2025
The role of IFNAR2 in regulation of damage during A. fumigatus lung infection - 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.
HHS’ Tracking Accountability in Government Grants System (TAGGS) website provides access to detailed descriptions of grants, loans, aggregated direct payments and other types of financial assistance awarded by the HHS Operating Divisions (OPDIVs) and the Office of the Secretary Staff Divisions (STAFFDIVs).