Aspergillus fumigatus persists within alveolar macrophages to drive chronic aspergillosis

About This Grant

Aspergillus fumigatus causes an array of respiratory diseases ranging from acute invasive aspergillus to allergic sensitization from chronic colonization. Allergic bronchopulmonary aspergillosis (ABPA) is one of the most severe and devasting chronic diseases caused by Aspergillus fumigatus. ABPA is particularly important in people with Cystic Fibrosis (pwCF) as it is associated with worsening lung function and increased frequency of exacerbations in those individuals. ABPA is associated with fungal persistence in the lungs, ultimately leading to fungal sensitization, characterized by high total serum IgE levels, as well as a large increase in airway Th2 cytokines that drive airway eosinophilia. Currently, there is a critical knowledge gap in our understanding of the host-pathogen interactions which enable certain Aspergillus fumigatus strains to persist long-term in the lungs thus driving fungal sensitization and ABPA disease progression. In collaboration with colleagues within the Dartmouth Cystic Fibrosis Research Center (DartCF) we have developed a novel ABPA murine model, which we will use to understand both the fungal and host factors enabling fungal persistence and ABPA disease initiation and progression. This proposal fills the aforementioned knowledge gap by examining both the role host lung-resident macrophages in establishing a protective, long-term survival niche for fungal persistence and alterations in fungal resistance to antifungal killing by those same lung-resident macrophages can alter ABPA disease initiation and progression. In SA1, we will determine the fungal- intrinsic pathways enabling Aspergillus fumigatus to persist in those lung-resident alveolar macrophages. Moreover, we will utilize a library of clinical Aspergillus fumigatus isolates from pwCF to determine if there is a selection of these pathways. In SA2, we examine the host pathways within the lung-resident alveolar macrophages which are responsible for long-term persistence of those cells after Aspergillus fumigatus engagement using classic immunological techniques (e.g. conditional knock-out mice and adoptive transfers) and a novel pooled genetic screen. Finally, we seek to provide proof-of- concept data that targeting these lung-resident macrophage populations could alter the disease course of ABPA in our mouse model. Together, these data will provide novel insights into mechanisms of fungal persistence which aids in the development and progression of ABPA in mammals. Overall, this research fills a critical gap by providing the field with a better understanding of how fungal traits beyond allergen expression may regulate chronic allergic fungal diseases, like APBA, while also identifying a unique host-targeted therapeutic approach to limit Aspergillus fumigatus persistence within the lungs of a mammalian host to ameliorate chronic fungal disease.