Single cell analysis reveals transcriptional changes underlying neurological complications in tuberculous meningitis

Tuberculous meningitis (TBM) is the most severe and deadly manifestation of tuberculosis. Neurological complications, e.g., hydrocephalus are observed in up to 50% of patients affected. The study of TBM pathogenesis is hampered, at least partially, by a lack of experimental models that recapitulate all clinical features of the human disease. With single-cell transcriptome of blood in tuberculosis revealed, the single cell transcriptome atlas in TBM brain remains yet to be explored. Here, a TBM model was built and then whole brain was dissected for single cell sequencing. Transcriptional changes were observed in all cell types, suggesting a complex biology in TBM pathogenesis. As a result, pervasive immune response was activated by transcription factors Stat1 and IRF1 in macrophages and microglia. For neurons, decreased oxidative phosphorylation activity in neurons links TBM with neurodegenerative diseases. Finally, Ependymal cells show most remarkable transcriptional changes, and decreased Frmd4a may contribute to hydrocephalus and neurodegenerative disorders. We first revealed a comprehensive transcriptome map in TBM mouse model with ScRNA-Seq, and link the cell types, transcriptional genes with regulons and functional processes with neurological complications. These identified cellular and molecular changes offer an unprecedented clue for inspiring the clinical diagnosis and therapeutics of TBM. Overall design: All twenty-four 6-week C57BL6 mice were used in TBM model and control groups. To acquire a representative TBM expression of each group, 6 mice were pooled together for the folleowing examinations. Each group were composed of two pooled samples: Control group (Ctrl-brain-1 and Ctrl-brain-2) and TBM group (TBM-brain-1 and TBM-brain-2)