Molecular Evidence of Mycobacterium tuberculosis Persistence in the Human and Murine Brain

Mycobacterium tuberculosis is primarily a pulmonary pathogen capable of systemic dis-semination and persistence in extrapulmonary tissues, perhaps including also the brain. To investigate this potential reservoir, we analyzed human brainstem samples from 50 forensic autopsies and brain tissue from a murine model of latent tuberculosis using PCR, RT-PCR, and RNA sequencing. Mycobacterial IS6110 insertion sequence and 16S rRNA were detected in 12/50 human samples and in all murine brains, confirming persistence. Variable expression of mycobacterial latency-associated (dosR, dosT, hspX, icl) and met-abolic adaptation genes (glcB, pcaA, phoP, mprA, treS) indicated heterogeneous dorman-cy states. Differential expression analysis revealed 19 modulated genes in human brain-stems (9 upregulated, 10 downregulated) and 2,700 in murine brains (1,509 upregulated, 1,191 downregulated). Metallothioneins, USP9(Y/X), and RAB27B showed similar expres-sion in human and mice brain tissue, whereas MAPK15 and calbindin2 displayed dis-cordant patterns. Functional enrichment in mice demonstrated a shift from resident neu-ral cell identity, activating translational and mitochondrial pathways while repressing synaptic signaling. These findings provide molecular evidence that M. tuberculosis per-sists in the central nervous system in a dormancy-associated state. The observed synaptic repression overlaps with neurodegenerative processes, whereas concurrent translational activation suggests a distinct adaptive host response, highlighting the need to explore chronic neuroinflammation linked to bacterial persistence.