Heterogeneous immune responses of the alveolar macrophage population during pulmonary fungal infections

PROJECT SUMMARY/ABSTRACT Alveolar macrophages (AMs) are lung-resident macrophages. They are one of the cell types that first encounter inhaled fungal pathogens. Currently, the role of AMs in fungal infections is still elusive; some articles reported AMs to be protective, but others showed them detrimental. The challenge to study AMs is that identification and evaluation of AMs in vivo require technologies such as; multi-color flow cytometry, reporter and fate-mapping (FM) mouse systems, and single cell-level of gene expression analyses. By using these technologies, we will elucidate the biological functions of AMs during pulmonary fungal infections. We recently demonstrated that AMs are the bona fide immune sentinels that respond to fungal infections and also elicit heterogeneous immune responses. In particular, fungal infections generate pro- and anti- inflammatory AM subpopulations simultaneously, and AM subpopulations with distinct functions co-exist in the infected lung. Such heterogeneity within the AM population cannot be elicited by pulmonary instillation of Toll- like recent ligands, suggesting possible specificity in fungal infections, likely through C-tyle lectin receptor signaling. The central hypothesis of this proposed study is: AMs develop into pro- and anti-inflammatory AMs in vivo at the level of transcriptional and epigenetic regulations, respectively. The generation of AM subpopulations with dichotomous functions is considered to maximize fungal clearance and minimize collateral damage in the lung. The objective of this proposed study is to identify the biological implication of functionally distinct AM subpopulations and to elucidate the detailed molecular mechanism by which the heterogeneous AM subpopulations are generated, maintained, and lost during fungal infections in vivo.