Cerebrospinal fluid transcriptional immune pathways linked to survival in HIV-associated tuberculous meningitis
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BACKGROUND
TB 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.
METHODS
We 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.
RESULTS
Among 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 .
CONCLUSIONS
A 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.
