Time-resolved multi-omics reveals macrophage-centered immunometabolic remodeling in cutaneous dematiaceous fungal infection

作者：Yongqiang Fu, Mengying Liu, Qi Dong, Xinyu Guo, Jun Lu, Weiwei Wu, Hiroki Takahashi, Ruijun Zhang · 发表于：Frontiers in Immunology · 年份：2026 · DOI：10.3389/fimmu.2026.1893423 · 研究领域：Fungal Infections and Studies、Antifungal resistance and susceptibility、Nail Diseases and Treatments

Background Dematiaceous fungi cause chronic, invasive cutaneous infections that are difficult to eradicate and frequently relapse despite antifungal therapy. Although host immunity is critical for controlling these infections, the temporal organization of immune responses and the underlying immunometabolic programs remain poorly defined. In particular, how macrophage dynamics and chemokine signaling shape antifungal immunity over time is largely unknown. Methods Using Phialophora verrucosa as a representative dematiaceous fungus, we established a murine subcutaneous infection model and performed time-resolved transcriptomic and proteomic analyses across the course of infection. Immune cell composition, pathway dynamics, and metabolic signatures were systematically characterized. To functionally validate key regulatory axes identified by multi-omics analyses, bone marrow–derived macrophages and dendritic cells from wild-type and Ccr2 knockout mice were subjected to in vitro fungus–cell coculture assays. Results Time-resolved multi-omics analysis revealed that days 7–14 post-infection constituted a critical transition phase of the host immune response, coinciding with lesion regression and pathogen clearance. This stage featured marked activation of pathways governing antigen presentation, phagosome formation and inflammatory signaling. Macrophages underwent dynamic changes in both abundance and phenotype during this period, accompanied by the upregulation of glycolysis- and la...