title: Modeling Mycobacterium tuberculosis early granuloma formation in experimental human lung tissue.
abstract: The widely used animal models for tuberculosis (TB) display fundamental differences from human TB. Therefore, a validated model that recapitulates human lung TB is attractive for TB research. Here, we describe a unique method for establishment of TB infection in an experimental human lung tissue model. The model is based on cell lines derived from human lungs and primary macrophages from peripheral blood, and displays characteristics of human lung tissue, including evenly integrated macrophages throughout the epithelium, production of extracellular matrix, stratified epithelia and mucus secretion. Establishment of experimental infection in the model tissue with Mycobacterium tuberculosis, the bacterium that causes TB, resulted in clustering of macrophages at the site of infection, reminiscent of early TB granuloma formation. We quantitated the extent of granuloma formation induced by different strains of mycobacteria and validated our model against findings in other TB models. We found that early granuloma formation is dependent on ESAT-6, which is secreted via the type VII secretion machinery of virulent mycobacteria. Our model, which can facilitate the discovery of the interactions between mycobacteria and host cells in a physiological environment, is the first lung tissue model described for TB.
authors.affiliation: Center for Infectious Medicine, Department of Medicine, Karolinska Institute, Stockholm 14186, Sweden.
authors.forename: Venkata Ramanarao
authors.initials: VR
authors.lastname: Parasa
authors.forename: Muhammad Jubayer
authors.initials: MJ
authors.lastname: Rahman
authors.forename: Anh Thu
authors.initials: AT
authors.lastname: Ngyuen Hoang
authors.forename: Mattias
authors.initials: M
authors.lastname: Svensson
authors.forename: Susanna
authors.initials: S
authors.lastname: Brighenti
authors.forename: Maria
authors.initials: M
authors.lastname: Lerm
mesh_terms: D000942:Antigens, Bacterial / Q000378:metabolism; D001426:Bacterial Proteins / Q000378:metabolism; D002449:Cell Aggregation; D006099:Granuloma / Q000382:microbiology* / Q000473:pathology*; D006801:Humans; D008168:Lung / Q000382:microbiology* / Q000473:pathology*; D008198:Lymph Nodes / Q000382:microbiology / Q000473:pathology; D008264:Macrophages / Q000473:pathology; D008954:Models, Biological; D009000:Monocytes / Q000473:pathology; D009169:Mycobacterium tuberculosis / Q000472:pathogenicity*; D009336:Necrosis; D014376:Tuberculosis / Q000382:microbiology / Q000473:pathology*; D014774:Virulence
chemical_list: D000942:Antigens, Bacterial; D001426:Bacterial Proteins; C093276:ESAT-6 protein, Mycobacterium tuberculosis
keywords: ESX-1; Granuloma; In vitro model; Lung tissue; M. tuberculosis; Tuberculosis