Contribution of cytotoxic CD8 T cells, neutrophils and type 1 interferon signaling to hyperinflammatory pathology in HIV associated TB meningitis [TBM_scRNAseq]

Immune dysregulation contributes to death and disability in tuberculous meningitis. People living with HIV have the highest risk of TBM, greatest death and disability, and the least evidence that anti-inflammatory therapy improves the poor outcome. Improving therapy relies on a more refined understanding of the host immune response. Using single-cell RNA sequencing, we characterised 188,983 lumbar CSF cells from 25 adults with HIV-associated TBM and identified correlates of bacterial load. There was heterogeneity in cell composition between patients, but cytotoxic CD8 T cells with low cytokine expression were consistently predominant with a large number expressing GZMK, known to activate complement. In microbiologically-confirmed TBM, there was greater cytotoxicity in T, NK and γδ cells, and higher type 1 interferon stimulation in T and B lymphocytes. Neutrophils expressed markers suggesting heightened cytokine stimulation, enhanced effector function, and IL-8-mediated peripheral neutrophil recruitment. In a separate longitudinal cohort, type 1 interferon signalling increased in the blood and CSF following treatment initiation. Overall, findings indicate a hyper-inflammatory immune response in the CSF of HIV-associated TBM patients characterised by an accumulation of granzyme-rich cytotoxic CD8 T cells, highly activated neutrophils and host-detrimental type 1 IFN signalling.