Linking Human Genotype And Immunological Phenotype To Understand Pathogenesis And Improve Treatment In TB


2017 – 2023

Principal Investigator: 
Associate Professor Nguyen Thuy Thuong Thuong

Pham Ngoc Thach Hospital
Hospital of Tropical Diseases
District TB Units in Ho Chi Minh City

This study aims to link human genotype and immunological phenotype to understand the pathogenesis and improve TB treatment.


The development of effective treatments for TB is hindered by a limited understanding of the disease pathogenesis. In general, host genetic variants regulate the immune response to infection and also drive the immunological pathogenesis of the disease, which can lead to poor outcomes.


This study will address three research questions:

How does dexamethasone therapy in tuberculous meningitis (TBM) influence transcriptional profiling of the immune response, bacterial clearance and survival/death?

We will look at blood and CSF cell types and explore whole-blood transcriptomic profiling using RNA-Seq. Transcriptional profiling data will be analysed together with bacterial killing data and survival outcomes to understand a wide spectrum of genetic and immunological factors in TB pathogenesis and the effectiveness of dexamethasone during TBM treatment.

Can the Leukotriene A4 hydrolase (LTA4H) genotype be used to predict the inflammatory transcriptome in TBM? What additional genes linked to survival are associated with the inflammatory transcriptome?

RNA-Seq will be performed on blood from TBM patients with the three LTA4H genotypes to identify their blood transcriptional signatures. This allows us to:

  • confirm whether the LTA4H genotype can be a predictor of treatment responsiveness;
  • strengthen understanding of the gene’s biological role in inflammation;
  • link quantity of gene expression and host genotype for novel genes involved in immune activities.

This work should yield new insights into TB disease pathophysiology and treatment optimisation.

What host variants and transcriptional immune responses are associated with bacterial killing and poor outcomes in pulmonary TB?

We will investigate the alteration of the transcriptome during TBM and PTB treatment. Clinical outcomes (treatment response, relapse, and failure) will be analysed together with transcriptome data to better understand immune pathogenesis, identify potential biomarkers of TB pathogenesis and determine the influence of host genotype on treatment response.

Shah JA, Warr AJ, Graustein AD, Saha A, Dunstan SJ, Thuong NTT, Thwaites GE, Caws M, Thai PVK, Bang ND, Chau TTH, Khor CC, Li Z, Hibberd M, Chang X, Nguyen FK, Hernandez CA, Jones MA, Sassetti CM, Fitzgerald KA, Musvosvi M, Gela A, Hanekom WA, Hatherill M, Scriba TJ, Hawn TR
J Immunol
Februari 25, 2022
DOI: 10.4049/jimmunol.2100671
Fiona V Cresswell, Angharad G Davis, Kusum Sharma, Robindra Basu Roy, Ahmad Rizal Ganiem, Enock Kagimu, Regan Solomons, Robert J Wilkinson, Nathan C Bahr, Nguyen Thuy Thuong Thuong, Tuberculous Meningitis International Research Consortium
Wellcome Open Res
Januari 28, 2021
DOI: 10.12688/wellcomeopenres.15506.3
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