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A polymorphism in human TLR2 is associated with increased susceptibility to tuberculous meningitis

Genes & Immunity volume 8, pages 422–428 (2007)Cite this article

Abstract

Tuberculous meningitis (TBM) results from the haematogenous dissemination of Mycobacterium tuberculosis from the lung to the brain. Dissemination is believed to occur early during infection, before the development of adaptive immunity. Toll-like receptor 2 (TLR2) mediates recognition of M. tuberculosis and initiates the innate immune response to infection. We hypothesized that polymorphisms in the TLR2 gene influence bacterial dissemination and the development of TBM. A case–control study was designed to test the hypothesis. Cases of bacteriologically confirmed pulmonary tuberculosis (TB) (n=183) and TBM (n=175), and cord blood controls (n=389) were enrolled in Vietnam. TLR2 genotype 597CC was associated with susceptibility to TB (odds ratio (OR)=2.22, 95% confidence interval (CI): 1.23−3.99). The association was found with meningeal rather than pulmonary TB (TBM vs control, OR=3.26, 95% CI: 1.72−6.18), and was strongest when miliary TB was found on chest radiography (controls vs TBM with miliary TB, OR=5.28, 95% CI: 2.20−12.65). Furthermore, the association increased with the severity of neurologic symptoms (grade I TBM, OR=1.93, 95% CI: 0.54−6.92; grade II, OR=3.32, 95% CI: 0.84−13.2; and grade III, OR=5.70, 95% CI: 1.81−18.0). These results demonstrate a strong association of TLR2 SNP T597C with the development of TBM and miliary TB and indicate that TLR2 influences the dissemination of M. tuberculosis.

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Acknowledgements

We acknowledge the directors and the staff of the Hospital for Tropical Disease, Pham Ngoc Thach Hospital for Tuberculosis and Lung Disease and Hung Vuong Hospital, Viet Nam for the clinical and microbiological work associated with this study. We thank the Vietnamese individuals who took part in this study. We also thank Marta Janer and Sarah Li (Institute of Systems Biology, USA) for expert assistance in genotyping. The Wellcome Trust and the DANA foundation funded this work.

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Authors and Affiliations

  1. Oxford University Clinical Research Unit, Hospital for Tropical Diseases, Ho Chi Minh City, Vietnam

    N T T Thuong, G E Thwaites, J J Farrar & S J Dunstan

  2. Hospital for Tropical Diseases, Ho Chi Minh City, Vietnam

    N T T Thuong, T T H Chau & T T Hien

  3. University of Washington School of Medicine, Seattle, WA, USA

    T R Hawn

  4. Institute for Systems Biology, Seattle, WA, USA

    T R Hawn & A Aderem

  5. Centre for Molecular Microbiology and Infection, Imperial College, London, UK

    G E Thwaites

  6. Pham Ngoc Thach Hospital for Tuberculosis and Lung Disease, Ho Chi Minh City, Vietnam

    N T N Lan & H T Quy

  7. Hung Vuong Obstetric Hospital, Ho Chi Minh City, Vietnam

    N T Hieu

  8. Nuffield Department of Clinical Medicine, Centre for Tropical Medicine, Oxford University, Oxford, UK,

    J J Farrar & S J Dunstan

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  1. N T T Thuong
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Correspondence to S J Dunstan.

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Thuong, N., Hawn, T., Thwaites, G. et al. A polymorphism in human TLR2 is associated with increased susceptibility to tuberculous meningitis. Genes Immun 8, 422–428 (2007). https://doi.org/10.1038/sj.gene.6364405

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  • DOI: https://doi.org/10.1038/sj.gene.6364405

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