Work

Inflammatory cellular transcriptome unravels drivers of clearance and pathology processes during cryptococcal meningoencephalitis 3863

Year: 2025

Type: article

Abstract: Description Dysregulated inflammation drives neuronal damage in cryptococcal meningitis (CM). To elucidate cell subsets’ contributions, single-cell transcriptome of CNS leukocytes was analyzed over time in a highly inflammatory CM mouse model (C57BL6/52D) and partially protected CXCR3-/- CM mice, using 10X platform. Inflammatory module score increases initially in microglia (Mg) followed by macrophages (Mp), and T cells (T), marking Mg as first-responders. Over time 14 Mg clusters show sequential cluster replacements and proliferation and their increased antigen presentation capacity. Among 13 gradually expanding T clusters, some helper and cytotoxic T expansion coincides with CM pathology. The 10 distinct Mp clusters represent the resident brain Mp and both recruited classical and non-classical monocytes with rapidly evolving signatures. Early Mp show antigen processing and presentation, chemokine and TNF-signaling, while JAK/STAT, MAPK and NF-kB signaling, and metabolic regulation pathways dominate later. Enrichment in Mp pathways linked to neurodegenerative diseases reflects their long-term impact on neuronal health and CNS-tissue integrity. Reduced Mp and cytotoxicity T-linked pathways in CXCR3-/- CM mice support their joint involvement in immunopathology. Finally, the diversity and strength of cell-cell interactions peak on days 7&14, preceding the peak in overall inflammatory cell scores, marking a dropout of proper immunoregulatory crosstalk during the ongoing inflammatory damage. Funding Sources This work was supported by VA RCS IK6BX005966, VA Merit 101BX000656, VA 121BX006349 Awards to MAO, and VA CDA2 Award to KG. Topic Categories Neuroimmunology (NEUR)

Source: The Journal of Immunology

DOI: 10.1093/jimmun/vkaf283.1615