Whole blood transcriptional profiles and the pathogenesis of tuberculous meningitis

Area of Science:

• Immunology
• Genetics
• Infectious Diseases

Background:

• Tuberculous meningitis (TBM) causes significant mortality and morbidity, largely due to inflammation from Mycobacterium tuberculosis.
• The precise mechanisms driving TBM pathogenesis and mortality remain incompletely understood.
• Identifying genetic and pathway-level differences can illuminate disease progression and inform treatment.

Purpose of the Study:

• To identify genes and molecular pathways associated with TBM pathogenesis and mortality.
• To determine the most effective predictors of death in TBM patients.
• To explore differences in TBM molecular signatures between HIV-positive and HIV-negative individuals.

Main Methods:

• Whole-blood RNA sequencing was performed on 281 TBM patients, 295 pulmonary tuberculosis (PTB) patients, and 30 healthy controls.
• Weighted gene co-expression network analysis (WGCNA) was used to identify key genes and pathways.
• Multivariate Cox regression and logistic regression models were employed to identify mortality predictors.

Main Results:

• Distinct gene expression patterns and pathway associations with mortality were observed between HIV-positive and HIV-negative TBM patients.
• Increased neutrophil activation and decreased T and B cell activation were significantly associated with TBM mortality.
• Four genes (MCEMP1, NELL2, ZNF354C, CD4) emerged as strong predictors of TBM mortality.

Conclusions:

• TBM induces a systemic inflammatory response comparable to PTB, with specific immune dysregulations contributing to mortality.
• Identifying these molecular pathways and predictive genes offers insights into potential therapeutic strategies for TBM.
• A novel four-gene biomarker has been identified for predicting TBM patient outcomes.