Abstract Details

Title CSF Host Transcriptomics Identifies Unique Host Gene Expression Patterns Between Survivors and Non-survivors in Adult Patients with Tuberculosis Meningitis (TBM)

Topic Infectious Disease

Presentation(s) S25 - Diagnostics and Therapies in Infectious Diseases (4:18 PM-4:30 PM)

Poster/Presentation
Number 005

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.

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

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.

Authors/Disclosures
Martineau Louine, MD (UCSF) PRESENTER	Dr. Louine has nothing to disclose.
Michael R. Wilson, MD, FAAN (University of California San Francisco)	Dr. Wilson has received personal compensation in the range of $10,000-$49,999 for serving as an officer or member of the Board of Directors for Delve Bio. Dr. Wilson has stock in Delve Bio. The institution of Dr. Wilson has received research support from Genentech / Roche. The institution of Dr. Wilson has received research support from NIH. The institution of Dr. Wilson has received research support from UCSF Weill Institute for Neurosciences. The institution of Dr. Wilson has received research support from Novartis. The institution of Dr. Wilson has received research support from National Multiple Sclerosis Society. The institution of Dr. Wilson has received research support from Fanconi Anemia Research Foundation. The institution of Dr. Wilson has received research support from Department of Defense. Dr. Wilson has received intellectual property interests from a discovery or technology relating to health care. Dr. Wilson has received intellectual property interests from a discovery or technology relating to health care. Dr. Wilson has received personal compensation in the range of $10,000-$49,999 for serving as a Expert Witness with US Dept of Justice.
David R. Boulware, MD, MPH (University of Minnesota)	The institution of David R. Boulware, MD, MPH has received personal compensation in the range of $500-$4,999 for serving on a Scientific Advisory or Data Safety Monitoring board for Sfunga. David R. Boulware, MD, MPH has received publishing royalties from a publication relating to health care. David R. Boulware, MD, MPH has received personal compensation in the range of $0-$499 for serving as a Study Section with NIH.
Mary Karalius, MD (UCSF)	Dr. Karalius has nothing to disclose.
Shiyin Wang (UCSF)	No disclosure on file
Darlisha Williams	No disclosure on file
Nathan Bahr	No disclosure on file
Fiona Cresswell	No disclosure on file
David Meya	No disclosure on file
Ravi Dandekar	No disclosure on file
Kelsey Zorn	No disclosure on file
Maham Zia (UCSF)	No disclosure on file
Charles Langelier	No disclosure on file
Eran Mick (UCSF)	No disclosure on file
Biyue Dai	No disclosure on file
Chloe Gerungan	No disclosure on file
Kristoffer E. Leon, MD, PhD (University of California, San Francisco)	Dr. Leon has nothing to disclose.