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

肺部真菌感染期间肺泡巨噬细胞群的异质免疫反应

• 批准号: 10688042
• 负责人: Mari L. Shinohara
• 金额: $ 51.78万
• 依托单位: DUKE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-09-24 至 2026-08-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10688042
• 关键词: ATAC-seq; Alveolar Macrophages; Anti-Inflammatory Agents; Antifungal Agents; Aspergillus fumigatus; Biological; Biological Process; CXCL2 gene; Cell Wall; Cells; Chemotactic Factors; Chromatin; Color; Cryptococcus; Cryptococcus neoformans; Epigenetic Process; Epithelial Cells; Equilibrium; Evaluation; Flow Cytometry; Gene Expression; Gene Expression Profiling; Generations; Genes; Genus Hippocampus; Growth; Heterogeneity; Hour; Immune; Immune response; Immunity; Infection; Inflammation; Inflammatory; Inhalation; Lectin Receptors; Ligands; Lung; Macrophage; Maps; Mediating; Messenger RNA; Molecular; Mus; Mutant Strains Mice; Mycoses; Patients; Play; Population; Predisposition; Receptor Signaling; Reporter; Reporting; Resolution; Role; Sentinel; Specificity; Structure of parenchyma of lung; System; TLR2 gene; TLR4 gene; Technology; Transcriptional Regulation; beta-Glucans; cell type; chemokine; dectin 1; epigenetic regulation; in vivo; neutrophil; new technology; novel; novel therapeutic intervention; pathogenic fungus; pharmacologic; reconstitution; response; single-cell RNA sequencing

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.

项目总结/摘要 肺泡巨噬细胞（AM）是肺驻留巨噬细胞。它们是一种细胞类型 遇到吸入的真菌病原体。目前，AM在真菌感染中的作用仍然难以捉摸;一些文章 报告AM是保护性的，但其他人显示它们有害。研究AM的挑战在于， 体内AM鉴定和评价需要诸如多色流式细胞术、报告基因和 命运作图（FM）小鼠系统和单细胞水平的基因表达分析。通过使用这些 技术，我们将阐明AM在肺部真菌感染中的生物学功能。 我们最近证明AM是真正的免疫哨兵，对真菌感染作出反应 并且还引发异质性免疫应答。特别是，真菌感染会产生亲和抗- 炎性AM亚群同时存在，并且具有不同功能的AM亚群共存于炎性细胞中。 肺部感染AM人群中的这种异质性不能通过肺内滴注Toll-1引起。 与最近的配体一样，提示可能通过C型凝集素受体在真菌感染中具有特异性 信号 这项研究的中心假设是：AM在体内发育成促炎和抗炎AM。 分别在转录和表观遗传调节水平上对体内的表达进行调节。AM亚群的产生 被认为具有二分功能，以最大限度地清除真菌，并最大限度地减少附带损害， 肺。这项研究的目的是确定功能不同的AM的生物学意义 亚群，并阐明详细的分子机制，异质性AM 亚群在体内真菌感染期间产生、维持和丢失。