Cerebrospinal fluid transcriptional immune pathways linked to survival in HIV-associated tuberculous meningitis

BACKGROUNDTB meningitis (TBM) has up to 50% mortality in people living with HIV. We investigated differences in cerebrospinal fluid (CSF) host immune responses associated with acute mortality. METHODSWe enrolled a prospective cohort of adults with definite, probable and possible HIV-related TBM, without evidence of co-infection, in Kampala, Uganda. We performed metagenomic next-generation sequencing (mNGS) of bulk CSF RNA to profile host gene expression and exclude participants with co-infecting or alternate central nervous system pathogens. We then assessed host differential gene expression based on 14-day mortality within the refined cohort. RESULTSAmong the 110 patients included in the transcriptomic analysis, 22.7% (n=25) died within 14 days of enrollment. More than 2000 genes were differentially expressed in the CSF based on 14-day mortality (adjusted p-value < 0.05). Genes upregulated in TBM-survivors included genes related to T-cell receptor signaling (LCK, FYN, LAT), T-cell survival and differentiation (IL7, CD27, IL12RB1), B-cell receptor signaling (BCR, CD81, PLCG2), and TNF signaling. Survivors demonstrated downregulation in the neutrophil chemoattractant gene CXCL1, and classical complement pathway genes C4A and C4B. CONCLUSIONSA regulated immune response in which T-cell, B-cell, and microglial signaling are upregulated, but also in which certain neutrophil and complement genes are downregulated, was associated with short-term TBM survival in this population with HIV-related TBM. This finding provides context for the nuanced immunologic response and suggests that certain targeted immunomodulatory agents may be more effective as adjunctive therapy in HIV-related TBM compared to broad spectrum agents such as glucocorticoids.