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Host gene-encoded severe lung TB: from genes to the potential pathways

Genes & Immunity volume 13, pages 605–620 (2012)Cite this article

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Abstract

We are reporting that the two-locus genotype −2518 macrophage chemoattractant protein (MCP)-1 GG and −1607 matrix metalloproteinase (MMP)-1 2G/2G promotes the expression of hyperinflammation in response to Mycobacterium tuberculosis infection, inducing extensive tissue damage and severe tuberculosis (TB) disease. Carriers of this two-locus genotype have a 13-fold higher chance of developing severe disease and 6.5-fold higher chance of developing permanent lesions, and a 3.864-fold higher chance of delayed response to first-line standardized treatment than carriers of any other relevant combination of genotypes at those two loci. Thus, these persons have an increased likelihood of poor health-related quality of life and of transmitting M. tuberculosis to other members of the community. In addition, through the analysis of human lung tissues, serum/plasma and in vitro experiments, including in vitro infections of THP-1 cells with M. tuberculosis and microarray analysis, we determined that this hyperinflammation state is potentially driven by the MCP-1/MMP-1/PAR-1 pathway. Hence, we are providing markers for the identification of TB cases that may develop severe pulmonary disease and delayed response to treatment, and are providing the basis for development of novel host-targeted clinical interventions to ameliorate the severity of pulmonary TB.

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Acknowledgements

We are grateful to all patients and healthy donors for their kind cooperation. We are grateful to Ms Maritza L Flores, study coordinator, for the superb work done and Dr Federico Monzon-Bordonaba and Mr Raul Gonzales for providing normal lung samples. We are grateful to Mr Philip Randall for his superb editorial assistance. We are grateful to Dr Edmond J Yunis in the Department of Pathology of Harvard Medical School and Dr Mauro Ferrari at The Methodist Hospital Research Institute for their superb leadership. We are grateful to the Peruvian Ministry of Health and the Peruvian National Institute of Health, both of which allowed appropriate access to the patients included in this study. We are grateful to the National Institutes of Health (NIH) and The Methodist Hospital Research Institute (TMHRI), both of which provided funding for this study. This work was supported by NIH grant R01 HL084347-06.

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Author notes

  1. M Ganachari and P O Flores-Villanueva: These authors contributed equally to this work.

Authors and Affiliations

  1. Center for Molecular and Translational Human Infectious Diseases Research, The Methodist Hospital Research Institute, Houston, TX, USA

    M Ganachari & P O Flores-Villanueva

  2. Department of Pathology and Genomic Medicine, The Methodist Hospital, Houston, TX, USA

    M Ganachari & P O Flores-Villanueva

  3. NGO ALBIOTEC, Lima, Peru

    H Guio

  4. Molecular and Immunology Laboratory, Peruvian National Institute of Health, Lima, Peru

    H Guio

  5. Cancer Pathology Laboratory, The Methodist Hospital Research Institute, Houston, TX, USA

    N Zhao

  6. Department of Pathology and Genomic Medicine, Hematopathology Section, The Methodist Hospital, Houston, TX, USA

    N Zhao

  7. Department of Immunology and Microbiology, Weill Cornell Medical College, New York, NY, USA

    P O Flores-Villanueva

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  1. M Ganachari
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Correspondence to P O Flores-Villanueva.

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Ganachari, M., Guio, H., Zhao, N. et al. Host gene-encoded severe lung TB: from genes to the potential pathways. Genes Immun 13, 605–620 (2012). https://doi.org/10.1038/gene.2012.39

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