Whole Blood Transcriptional Profiles Reveal Pathways Associated with Mortality in Tuberculous Meningitis

Core Concepts

Mortality from tuberculous meningitis is associated with increased neutrophil activation and decreased T and B cell activation pathways. A four-gene host response signature in blood can predict early mortality from tuberculous meningitis.

Abstract

The study used whole blood RNA sequencing to investigate the transcriptional profiles associated with mortality in 281 Vietnamese adults with tuberculous meningitis (TBM), 295 with pulmonary tuberculosis (PTB), and 30 healthy controls.
Key findings:

TBM mortality was associated with increased activation of inflammatory and innate immune response pathways, particularly those involving neutrophil activation, and decreased activation of adaptive immunity pathways involving T and B cell responses.

Specific gene modules and hub genes were identified that were strongly associated with TBM mortality. These included upregulation of genes involved in acute inflammation and neutrophil activation (e.g. MCEMP1, FCAR), and downregulation of genes involved in T and B cell signaling (e.g. NELL2, TRABD2A, PLCG1, CD247).

The association of these pathways and hub genes with mortality differed somewhat between HIV-positive and HIV-negative TBM. In HIV-positive TBM, mortality was associated with increased angiogenesis, while in HIV-negative TBM it was associated with increased TNF signaling and decreased extracellular matrix organization.

A four-gene host response signature in blood (MCEMP1, NELL2, ZNF354C, CD4) was highly predictive of three-month mortality in both HIV-negative and HIV-positive TBM, with an AUC of 0.80 and 0.86 respectively.

These findings provide novel insights into the pathogenesis of TBM and identify potential prognostic biomarkers that could help guide treatment of this lethal disease.

Stats

"Mortality was associated with higher peripheral blood neutrophil counts and lower lymphocyte counts."
"Overall three-month mortality rate was 21.7% (61/281) for TBM, 16.4% (34/207) in HIV-negative and 36.5% (27/74) in HIV-positive TBM."

Quotes

"Mortality and morbidity from tuberculous meningitis (TBM) are frequent and strongly associated with the inflammatory response to Mycobacterium tuberculosis infection."
"The poor outcomes from TBM are strongly associated with the inflammatory response, with both a paucity and an excess of inflammation linked to death from TBM."
"Host-based peripheral blood gene expression analysis has been used to identify active or progressive pulmonary TB and in pulmonary TB treatment monitoring, but has yet to be applied to TBM."

Key Insights Distilled From

Whole blood transcriptional profiles and the pathogenesis of tuberculous meningitis

by Hai,H. T., T... at www.biorxiv.org 10-09-2023

https://www.biorxiv.org/content/10.1101/2023.10.06.561265v4

Deeper Inquiries

What are the potential therapeutic implications of the identified differences in inflammatory pathways between HIV-positive and HIV-negative TBM patients

The identified differences in inflammatory pathways between HIV-positive and HIV-negative TBM patients have significant therapeutic implications. For HIV-positive individuals, the upregulation of angiogenesis pathways associated with mortality suggests a potential target for intervention. Angiogenesis plays a crucial role in inflammation and tissue repair, and its dysregulation can contribute to disease progression. Targeting angiogenesis pathways in HIV-positive TBM patients could help modulate the inflammatory response and potentially improve outcomes. Additionally, the differences in TNF signaling between HIV-positive and negative individuals highlight the need for tailored therapeutic approaches. TNF signaling is a key mediator of inflammation and immune responses, and targeting this pathway could be beneficial in managing the inflammatory cascade in TBM patients, especially those with HIV.

How might the four-gene host response signature be further validated and incorporated into clinical practice to guide treatment decisions for TBM patients

The four-gene host response signature identified in this study holds promise as a prognostic biomarker for TBM patients. To further validate and incorporate this signature into clinical practice, several steps can be taken. Firstly, the signature should be validated in independent cohorts to confirm its predictive value across different populations. This validation process should include diverse patient groups to ensure the generalizability of the signature. Once validated, the signature can be integrated into clinical decision-making algorithms for TBM patients. Clinicians can use the signature to stratify patients based on their risk of mortality, allowing for personalized treatment approaches. Additionally, the signature can be used to monitor treatment response and adjust therapy accordingly. Incorporating the four-gene host response signature into clinical practice has the potential to improve patient outcomes and optimize TBM management.

What are the potential mechanisms by which the identified hub genes and pathways contribute to the pathogenesis of TBM, and could these provide novel targets for therapeutic intervention

The identified hub genes and pathways play crucial roles in the pathogenesis of TBM and offer potential targets for therapeutic intervention. The upregulated hub genes associated with acute inflammation, such as MCEMP1 and FCAR, are indicative of an exaggerated immune response in TBM patients. Targeting these genes or pathways could help modulate the inflammatory cascade and prevent excessive tissue damage. On the other hand, the downregulated hub genes involved in adaptive immunity, like CD4 and NELL2, suggest an impairment in immune responses that are essential for controlling Mycobacterium tuberculosis infection. Developing therapies that enhance adaptive immune responses or restore immune function could be beneficial in TBM treatment. Additionally, the pathways identified, such as TNF signaling and angiogenesis, provide potential targets for therapeutic intervention. Modulating these pathways could help regulate the inflammatory response and improve patient outcomes in TBM. Overall, the hub genes and pathways identified in this study offer novel insights into TBM pathogenesis and present opportunities for the development of targeted therapies.