title: Tuberculous granuloma induction via interaction of a bacterial secreted protein with host epithelium.
abstract: Granulomas, organized aggregates of immune cells, are a hallmark of tuberculosis and have traditionally been thought to restrict mycobacterial growth. However, analysis of Mycobacterium marinum in zebrafish has shown that the early granuloma facilitates mycobacterial growth; uninfected macrophages are recruited to the granuloma where they are productively infected by M. marinum. Here, we identified the molecular mechanism by which mycobacteria induce granulomas: The bacterial secreted protein 6-kD early secreted antigenic target (ESAT-6), which has long been implicated in virulence, induced matrix metalloproteinase-9 (MMP9) in epithelial cells neighboring infected macrophages. MMP9 enhanced recruitment of macrophages, which contributed to nascent granuloma maturation and bacterial growth. Disruption of MMP9 function attenuated granuloma formation and bacterial growth. Thus, interception of epithelial MMP9 production could hold promise as a host-targeting tuberculosis therapy.
authors.affiliation: Molecular and Cellular Biology Graduate Program, University of Washington, Seattle, WA 98155, USA.
authors.forename: Hannah E
authors.initials: HE
authors.lastname: Volkman
authors.forename: Tamara C
authors.initials: TC
authors.lastname: Pozos
authors.forename: John
authors.initials: J
authors.lastname: Zheng
authors.forename: J Muse
authors.initials: JM
authors.lastname: Davis
authors.forename: John F
authors.initials: JF
authors.lastname: Rawls
authors.forename: Lalita
authors.initials: L
authors.lastname: Ramakrishnan
mesh_terms: D000818:Animals; D000942:Antigens, Bacterial / Q000235:genetics / Q000378:metabolism*; D001426:Bacterial Proteins / Q000235:genetics / Q000378:metabolism*; D004195:Disease Models, Animal; D004625:Embryo, Nonmammalian / Q000382:microbiology; D004790:Enzyme Induction; D004847:Epithelial Cells / Q000201:enzymology*; D006099:Granuloma / Q000378:metabolism / Q000382:microbiology*; D008264:Macrophages / Q000382:microbiology / Q000502:physiology; D020780:Matrix Metalloproteinase 9 / Q000235:genetics / Q000378:metabolism*; D009165:Mycobacterium Infections, Nontuberculous / Q000382:microbiology*; D019910:Mycobacterium marinum / Q000254:growth & development / Q000378:metabolism / Q000472:pathogenicity*; D009169:Mycobacterium tuberculosis / Q000235:genetics / Q000472:pathogenicity; D020320:Oligoribonucleotides, Antisense; D011994:Recombinant Proteins / Q000378:metabolism; D014376:Tuberculosis / Q000382:microbiology*; D037521:Virulence Factors / Q000235:genetics / Q000378:metabolism*; D015027:Zebrafish / Q000196:embryology; D029961:Zebrafish Proteins / Q000235:genetics / Q000378:metabolism
chemical_list: D000942:Antigens, Bacterial; D001426:Bacterial Proteins; C093276:ESAT-6 protein, Mycobacterium tuberculosis; D020320:Oligoribonucleotides, Antisense; D011994:Recombinant Proteins; D037521:Virulence Factors; D029961:Zebrafish Proteins; D020780:Matrix Metalloproteinase 9