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<p><i>Aspergillus fumigatus</i> poses a critical threat to immunocompromised hosts through invasive aspergillosis, with mortality rates reaching 50–90%. Although macrophages initiate early antifungal defenses via pattern recognition receptors, the temporal dynamics of immune reprogramming remain incompletely characterized. This study integrated time-series transcriptomics (GSE202286) of human monocyte-derived macrophages exposed to <i>A. fumigatus</i> conidia (0–8&#xa0;h) with experimental validation to delineate immune-phase transitions and identify candidate regulatory modules. Bioinformatics analysis revealed a progressive increase in differential gene expression, peaking at 8&#xa0;h (2,636 upregulated and 1,940 downregulated genes). Gene set enrichment analysis (GSEA) showed early enrichment of TNF-α/NF-κB signaling (NES = 2.37, 2&#xa0;h), followed by a prominent interferon-γ response at 8&#xa0;h (NES = 2.37) that coincided with ongoing inflammatory pathway activity. Temporal clustering identified 448 dynamically regulated genes associated with oxidative stress response (GO:0006979) and exploratory C-type lectin receptor-related pathway patterns (KEGG hsa04625). Protein interaction and transcription factor analyses predicted STAT2 as a candidate upstream regulator associated with IRF1 and ISG15. qRT-PCR validation in THP-1-derived macrophages showed sequential mRNA induction, with <i>STAT2</i> peaking at 2&#xa0;h, <i>IRF1</i> at 4&#xa0;h, and <i>ISG15</i> remaining elevated through 8&#xa0;h. A representative Western blot further supported this temporal pattern, showing early STAT2 phosphorylation, subsequent IRF1 protein induction, and later accumulation of free ISG15. Together, these findings suggest a STAT2-IRF1-ISG15-associated transcriptional program that may contribute to the transition from an inflammatory to an interferon-augmented macrophage response during <i>A. fumigatus</i> challenge.</p>

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STAT2-IRF1-ISG15-Associated Temporal Immune Reprogramming in Macrophages during Aspergillus fumigatus Infection

  • 期刊论文

  • 发表日期：

    2026年6月20日

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  • Quan Zhou,
  • Rendong Li,
  • Dandan Song,
  • Xingping Xu,
  • Jianbo Tong

摘要

Aspergillus fumigatus poses a critical threat to immunocompromised hosts through invasive aspergillosis, with mortality rates reaching 50–90%. Although macrophages initiate early antifungal defenses via pattern recognition receptors, the temporal dynamics of immune reprogramming remain incompletely characterized. This study integrated time-series transcriptomics (GSE202286) of human monocyte-derived macrophages exposed to A. fumigatus conidia (0–8 h) with experimental validation to delineate immune-phase transitions and identify candidate regulatory modules. Bioinformatics analysis revealed a progressive increase in differential gene expression, peaking at 8 h (2,636 upregulated and 1,940 downregulated genes). Gene set enrichment analysis (GSEA) showed early enrichment of TNF-α/NF-κB signaling (NES = 2.37, 2 h), followed by a prominent interferon-γ response at 8 h (NES = 2.37) that coincided with ongoing inflammatory pathway activity. Temporal clustering identified 448 dynamically regulated genes associated with oxidative stress response (GO:0006979) and exploratory C-type lectin receptor-related pathway patterns (KEGG hsa04625). Protein interaction and transcription factor analyses predicted STAT2 as a candidate upstream regulator associated with IRF1 and ISG15. qRT-PCR validation in THP-1-derived macrophages showed sequential mRNA induction, with STAT2 peaking at 2 h, IRF1 at 4 h, and ISG15 remaining elevated through 8 h. A representative Western blot further supported this temporal pattern, showing early STAT2 phosphorylation, subsequent IRF1 protein induction, and later accumulation of free ISG15. Together, these findings suggest a STAT2-IRF1-ISG15-associated transcriptional program that may contribute to the transition from an inflammatory to an interferon-augmented macrophage response during A. fumigatus challenge.