Whole blood transcriptional profiles and the pathogenesis of tuberculous meningitis

Author:

Hai Hoang Thanh1ORCID,Nhat Le Thanh Hoang1ORCID,Tram Trinh Thi Bich1,Vinh Do Dinh1,Nath Artika P2,Donovan Joseph13,Thu Nguyen Thi Anh1,Van Thanh Dang1,Bang Nguyen Duc4,Ha Dang Thi Minh4,Phu Nguyen Hoan15,Nghia Ho Dang Trung156,Van Le Hong1,Inouye Michael27ORCID,Thwaites Guy E13ORCID,Thuong Nguyen Thuy Thuong13

Affiliation:

1. Oxford University Clinical Research Unit

2. Cambridge Baker Systems Genomics Initiative, Baker Heart and Diabetes Institute

3. Centre for Tropical Medicine and Global Health, Nuffield Department of Medicine, University of Oxford

4. Pham Ngoc Thanh Hospital

5. Hospital for Tropical Diseases

6. Pham Ngoc Thach University of Medicine

7. Cambridge Baker Systems Genomics Initiative, Department of Public Health and Primary Care, University of Cambridge

Abstract

Mortality and morbidity from tuberculous meningitis (TBM) are frequent and strongly associated with the inflammatory response to Mycobacterium tuberculosis infection. However, the mechanisms driving the associations are uncertain. We sought to identify the gene modules, hubs and pathways associated with the pathogenesis and mortality from TBM, and to identify which best-predicted death.We used whole blood RNA sequencing to obtain transcriptional profiles from 281 Vietnamese adults with TBM (207 HIV-negative; 74 HIV-positive), 295 with pulmonary TB (PTB), and 30 healthy controls. The TBM cohort was divided randomly into a discovery cohort (n=142) and a validation cohort (n=139). Weighted gene co-expression network analysis identified clusters of genes (or ‘modules’) and hub genes associated with death or disease severity. An overrepresentation analysis identified pathways associated with TBM mortality, with a consensus analysis identifying consensual patterns between HIV-positive and HIV-negative individuals. A multivariate elastic-net Cox regression model selected the candidate predictors of TBM mortality, then model prediction performance using logistic regression and internal bootstrap validation to choose best predictors.Overall, TBM mortality was associated with increased neutrophil activation and decreased T and B cell activation pathways. Death from TBM was associated with increased angiogenesis in HIV-positive adults, and with activated TNF signaling and down-regulated extracellular matrix organization in HIV-negative adults. PTB and TBM have similar transcriptional profiles compared to healthy controls, although inflammatory genes were more activated in HIV-positive than HIV-negative TBM. The expression of four hub genes – MCEMP1 , NELL2 , ZNF354C and CD4 – were strongly predictive of death from TBM (AUC 0.80 and 0.86 for HIV-negative and HIV-positive, respectively).Whole blood transcriptional profiling revealed that TBM is associated with a characteristic systemic inflammatory response, similar to that invoked by pulmonary tuberculosis, but with key gene modules, hubs and pathways strongly associated with death. Our analysis suggests a novel 4-gene biomarker for predicting death from TBM, but also opens a new window into TBM pathogenesis that may reveal novel therapeutic targets for this lethal disease.

Publisher

eLife Sciences Publications, Ltd

Reference48 articles.

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