CSF Host Transcriptomics Identifies Unique Host Gene Expression Patterns Between Survivors and Non-survivors in Adult Patients with Tuberculosis Meningitis (TBM)
Martineau Louine1, Michael Wilson3, David Boulware4, Mary Rolfes2, Mary Wang2, Darlisha Williams5, Nathan Bahr5, Fiona Cresswell5, David Meya5, Ravi Dandekar2, Kelsey Zorn6, Maham Zia2, Charles Langelier2, Mick Eran2, Biyue Dai5, Chloe Gerungan2, Kristoffer Leon7
1Neurology, UCSF, 2UCSF, 3University of California San Francisco, 4University of Minnesota, 5University of Minessota, 6University of CA San Francisco, 7University of California, San Francisco
Objective:
We investigated cerebrospinal fluid (CSF) host transcriptomic differences in TBM survivors compared to non-survivors as a means of understanding the role that the host response plays in surviving TBM
Background:
Mycobacterium tuberculosis (TB) affects 10 million people worldwide with over 1.5 million deaths annually. TB meningitis (TBM) is the most severe presentation with up to 50% mortality in people with HIV.
Design/Methods:
We enrolled a prospective cohort of adults presenting with suspected TBM in Uganda. We defined TBM per consensus criteria as definite, probable, or possible TBM. Bulk RNA sequencing was performed on RNA extracted from admission CSF collected in nucleic acid preservative. Differential gene expression analysis identified differences between TBM survivors and non-survivors (adjusted p-value <0.05, fold change > |1|). The WEB-based GEne SeT AnaLysis Toolkit and gene set enrichment analysis identified molecular pathways enriched in TBM survivors and non-survivors.
Results:
CSF RNA-Seq was performed on participants with TBM who survived (n=51) and who died (n=27). The median age was 38 in both the survivor and non-survivor groups. 90% of patients were infected with HIV. The average CD4 count was 106 and 51 cells/mm3 in survivors and non-survivors, respectively. >3000 genes were differentially expressed, including upregulation of NFKB1, PDE4B and GMAP5 in survivors. Upregulated pathways in survivors included structural pathway interleukin 1 and the T cell receptor signaling pathway. NFKB1 plays an important role in both pathways. Gene set enrichment analysis similarly showed enrichment of cytokine production, including interferon-gamma, and the B cell receptor signaling pathway in survivors.
Conclusions:
Our findings suggest that a more robust innate and adaptive immune response in the CSF is associated with survival in this predominantly HIV+ cohort, suggesting that in this population, adjunctive steroids for TBM might not be as efficacious as in an immunocompetent population.