title: Host gene-encoded severe lung TB: from genes to the potential pathways.
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.
authors.affiliation: Center for Molecular and Translational Human Infectious Diseases Research, The Methodist Hospital Research Institute, Houston, TX 77030, USA.
authors.forename: M
authors.initials: M
authors.lastname: Ganachari
authors.forename: H
authors.initials: H
authors.lastname: Guio
authors.forename: N
authors.initials: N
authors.lastname: Zhao
authors.forename: P O
authors.initials: PO
authors.lastname: Flores-Villanueva
mesh_terms: D000328:Adult; D000995:Antitubercular Agents / Q000494:pharmacology / Q000627:therapeutic use; D015415:Biomarkers / Q000378:metabolism; D002460:Cell Line; D018932:Chemokine CCL2 / Q000235:genetics* / Q000378:metabolism; D024901:Drug Resistance, Multiple, Bacterial; D005260:Female; D005786:Gene Expression Regulation; D056426:Genetic Loci; D020022:Genetic Predisposition to Disease; D054884:Host-Pathogen Interactions; D006801:Humans; D007249:Inflammation / Q000188:drug therapy / Q000235:genetics / Q000382:microbiology; D008297:Male; D020781:Matrix Metalloproteinase 1 / Q000235:genetics* / Q000378:metabolism; D008875:Middle Aged; D009169:Mycobacterium tuberculosis / Q000187:drug effects / Q000502:physiology; D020641:Polymorphism, Single Nucleotide; D011401:Promoter Regions, Genetic; D044463:Receptor, PAR-1 / Q000235:genetics / Q000378:metabolism; D012720:Severity of Illness Index; D015398:Signal Transduction; D014397:Tuberculosis, Pulmonary / Q000188:drug therapy / Q000235:genetics* / Q000382:microbiology
chemical_list: D000995:Antitubercular Agents; D015415:Biomarkers; C111835:CCL2 protein, human; D018932:Chemokine CCL2; D044463:Receptor, PAR-1; D020781:Matrix Metalloproteinase 1