Single-cell analysis reveals changes in BCG vaccine-injected mice modeling tuberculous meningitis brain infection.

Tuberculous meningitis (TBM) is the most severe and deadly manifestation of tuberculosis. Neurological complications are observed in up to 50% of patients affected. Here, attenuated Mycobacterium bovis are injected into the cerebellum of mice, and histopathological images and cultured colonies confirm successful brain infection. Then, whole-brain tissue is dissected for 10X Genomics single-cell sequencing, and we acquire 15 cell types. Transcriptional changes of inflammation processes are found in multiple cell types. Specifically, Stat1 and IRF1 are shown to mediate inflammation in macrophages and microglia. For neurons, decreased oxidative phosphorylation activity in neurons is observed, which corresponds to TBM clinical symptoms of neurodegeneration. Finally, ependymal cells present prominent transcriptional changes, and decreased FERM domain containing 4A (Frmd4a) may contribute to TBM clinical symptoms of hydrocephalus and neurodegeneration. This study shows a single-cell transcriptome of M. bovis infection in mice and improves the understanding of brain infection and neurological complications in TBM.