Whole blood transcriptional profiles and the pathogenesis of tuberculous meningitis

• Published in: eLife 2024-10, Vol.13
• Main Authors: Hai, Hoang Thanh, Thanh Hoang Nhat, Le, Tram, Trinh Thi Bich, Vinh, Do Dinh, Nath, Artika P, Donovan, Joseph, Thu, Nguyen Thi Anh, Van Thanh, Dang, Bang, Nguyen Duc, Ha, Dang Thi Minh, Phu, Nguyen Hoan, Nghia, Ho Dang Trung, Van, Le Hong, Inouye, Michael, Thwaites, Guy E, Thuong Thuong, Nguyen Thuy
• Format: Article
• Language: English
• ISSN: 2050-084X; 2050-084X
• DOI: 10.7554/eLife.92344.3

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. 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 wh