Mortality and morbidity from tuberculous meningitis (TBM) are common, primarily due to inflammatory response to Mycobacterium tuberculosis infection, yet the underlying mechanisms remain poorly understood. We aimed to uncover genes and pathways associated with TBM pathogenesis and mortality, and determine the best predictors of death, utilizing whole-blood RNA sequencing from 281 Vietnamese adults with TBM, 295 pulmonary tuberculosis (PTB), and 30 healthy controls. Through weighted gene co-expression network analysis, we identified hub genes and pathways linked to TBM severity and mortality, with a consensus analysis revealing distinct patterns between HIV-positive and HIV-negative individuals. We employed multivariate elastic-net Cox regression to select candidate predictors of death, then logistic regression and internal bootstrap validation to choose best predictors. Increased neutrophil activation and decreased T and B cell activation pathways were associated with TBM mortality. Among HIV-positive individuals, mortality associated with increased angiogenesis, while HIV-negative individuals exhibited elevated TNF signaling and impaired extracellular matrix organization. Four hub genes-MCEMP1, NELL2, ZNF354C, and CD4-were strong TBM mortality predictors. These findings indicate that TBM induces a systemic inflammatory response similar to PTB, highlighting critical genes and pathways related to death, offering insights for potential therapeutic targets alongside a novel four-gene biomarker for predicting outcomes.
Keywords: human; immunology; infectious disease; inflammation; microbiology; mortality; pathogenesis; prognostic; tuberculous meningitis; whole blood RNA sequencing.
Tuberculous meningitis is a dangerous condition caused by the bacteria responsible for tuberculosis spreading from the lungs to the brain. It affects more than 150,000 adults a year worldwide, and results in death or brain damage in half of all patients. People living with HIV are particularly at risk for negative outcomes. These severe forms of tuberculous meningitis may be linked to the immune system becoming over-active while trying to fight the disease and harming the brain in the process. Detecting this hyperinflammation via blood sample analyzes has remained challenging so far, as traditional approaches can only offer partial information on the inflammatory response. In response, Hai, Nhat et al. took advantage of new genetic approaches to examine the expression of around 20,000 genes in the blood of HIV-positive and HIV-negative patients with tuberculous meningitis or lung tuberculosis, as well as in healthy individuals. Identifying which genes are more or less expressed in the different groups of volunteers can help to better understand the mechanisms associated with tuberculous meningitis, particularly in its most dangerous forms. Such analysis could also allow scientists to pinpoint which genes to monitor to efficiently detect patients at higher risk of severe complications. The results show that tuberculous meningitis mortality was associated with a distinct pattern of immune cell response; white blood cells known as neutrophils were increasingly activated while T and B cells showed decreased activity. Increased mortality was also linked to different patterns of gene activity between patients living with or without HIV. Overall, inflammatory genes were more activated in HIV-positive tuberculous meningitis patients than in their HIV-negative counterparts. Finally, Hai, Nhat et al. found that the blood activity levels of just four specific genes formed a signature associated with increased risk of death from tuberculous meningitis. In the future, medical professionals may be able to use this signature to rapidly identify patients who require intensive care and more specialized treatments. The findings also reveal immune system processes and molecules that may serve as potential drug targets for future therapies against this disease.
© 2024, Hai, Thanh Hoang Nhat et al.