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

Genes Immun. 2012 Dec;13(8):605-20. doi: 10.1038/gene.2012.39. Epub 2012 Sep 20.


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.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Adult
  • Antitubercular Agents / pharmacology
  • Antitubercular Agents / therapeutic use
  • Biomarkers / metabolism
  • Cell Line
  • Chemokine CCL2 / genetics*
  • Chemokine CCL2 / metabolism
  • Drug Resistance, Multiple, Bacterial
  • Female
  • Gene Expression Regulation
  • Genetic Loci*
  • Genetic Predisposition to Disease*
  • Host-Pathogen Interactions
  • Humans
  • Inflammation / drug therapy
  • Inflammation / genetics
  • Inflammation / microbiology
  • Male
  • Matrix Metalloproteinase 1 / genetics*
  • Matrix Metalloproteinase 1 / metabolism
  • Middle Aged
  • Mycobacterium tuberculosis / drug effects
  • Mycobacterium tuberculosis / physiology
  • Polymorphism, Single Nucleotide*
  • Promoter Regions, Genetic
  • Receptor, PAR-1 / genetics
  • Receptor, PAR-1 / metabolism
  • Severity of Illness Index
  • Signal Transduction
  • Tuberculosis, Pulmonary / drug therapy
  • Tuberculosis, Pulmonary / genetics*
  • Tuberculosis, Pulmonary / microbiology


  • Antitubercular Agents
  • Biomarkers
  • CCL2 protein, human
  • Chemokine CCL2
  • Receptor, PAR-1
  • Matrix Metalloproteinase 1