Host gene-encoded severe lung TB: from genes to the potential pathways
Open Access
- 20 September 2012
- journal article
- research article
- Published by Springer Science and Business Media LLC in Genes & Immunity
- Vol. 13 (8), 605-620
- https://doi.org/10.1038/gene.2012.39
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.Keywords
This publication has 46 references indexed in Scilit:
- Host Genotype-Specific Therapies Can Optimize the Inflammatory Response to Mycobacterial InfectionsCell, 2012
- Regulation of CCL2 Expression by an Upstream TALE Homeodomain Protein-Binding Site That Synergizes with the Site Created by the A-2578G SNPPLOS ONE, 2011
- MMP-1 drives immunopathology in human tuberculosis and transgenic miceJCI Insight, 2011
- Caseation of human tuberculosis granulomas correlates with elevated host lipid metabolismEMBO Molecular Medicine, 2010
- Joint Effect of MCP-1 Genotype GG and MMP-1 Genotype 2G/2G Increases the Likelihood of Developing Pulmonary Tuberculosis in BCG-Vaccinated IndividualsPLOS ONE, 2010
- The Role of the Granuloma in Expansion and Dissemination of Early Tuberculous InfectionCell, 2009
- Prep1/Pbx2 complexes regulate CCL2 expression through the −2578 guanine polymorphismGenes & Immunity, 2008
- Genetic Dissection of Immunity to Mycobacteria: The Human ModelAnnual Review of Immunology, 2002
- A Novel Polymorphism in the MCP-1 Gene Regulatory Region That Influences MCP-1 ExpressionBiochemical and Biophysical Research Communications, 1999
- Novel human immunodeficiencies reveal the essential role of type-1 cytokines in immunity to intracellular bacteriaImmunology Today, 1998