title: Role of Metal-Dependent Regulation of ESX-3 Secretion in Intracellular Survival of Mycobacterium tuberculosis.
abstract: More people die every year from Mycobacterium tuberculosis infection than from infection by any other bacterial pathogen. Type VII secretion systems (T7SS) are used by both environmental and pathogenic mycobacteria to secrete proteins across their complex cell envelope. In the nonpathogen Mycobacterium smegmatis, the ESX-1 T7SS plays a role in conjugation, and the ESX-3 T7SS is involved in metal homeostasis. In M. tuberculosis, these secretion systems have taken on roles in virulence, and they also are targets of the host immune response. ESX-3 secretes a heterodimer composed of EsxG (TB9.8) and EsxH (TB10.4), which impairs phagosome maturation in macrophages and is essential for virulence in mice. Given the importance of EsxG and EsxH during infection, we examined their regulation. With M. tuberculosis, the secretion of EsxG and EsxH was regulated in response to iron and zinc, in accordance with the previously described transcriptional response of the esx-3 locus to these metals. While iron regulated the esx-3 expression in both M. tuberculosis and M. smegmatis, there is a significant difference in the dynamics of this regulation. In M. smegmatis, the esx-3 locus behaved like other iron-regulated genes such as mbtB In M. tuberculosis, both iron and zinc modestly repressed esx-3 expression. Diminished secretion of EsxG and EsxH in response to these metals altered the interaction of M. tuberculosis with macrophages, leading to impaired intracellular M. tuberculosis survival. Our findings detail the regulatory differences of esx-3 in M. tuberculosis and M. smegmatis and demonstrate the importance of metal-dependent regulation of ESX-3 for virulence in M. tuberculosis.
authors.affiliation: Division of Infectious Diseases, Department of Medicine, New York University School of Medicine, New York, New York, USA.
authors.forename: Emir
authors.initials: E
authors.lastname: Tinaztepe
authors.affiliation: Department of Immunology and Infectious Diseases, Harvard T. H. Chan School of Public Health, Boston, Massachusetts, USA.
authors.forename: Jun-Rong
authors.initials: JR
authors.lastname: Wei
authors.affiliation: Division of Infectious Diseases, Department of Medicine, New York University School of Medicine, New York, New York, USA.
authors.forename: Jenelle
authors.initials: J
authors.lastname: Raynowska
authors.affiliation: Division of Infectious Diseases, Department of Medicine, New York University School of Medicine, New York, New York, USA.
authors.forename: Cynthia
authors.initials: C
authors.lastname: Portal-Celhay
authors.affiliation: Division of Infectious Diseases, Department of Medicine, New York University School of Medicine, New York, New York, USA.
authors.forename: Victor
authors.initials: V
authors.lastname: Thompson
authors.affiliation: Division of Infectious Diseases, Department of Medicine, New York University School of Medicine, New York, New York, USA jphilips@dom.wustl.edu.
authors.forename: Jennifer A
authors.initials: JA
authors.lastname: Philips
mesh_terms: D000818:Animals; D001426:Bacterial Proteins / Q000378:metabolism*; D015964:Gene Expression Regulation, Bacterial; D056426:Genetic Loci; D007501:Iron / Q000378:metabolism; D008264:Macrophages / Q000276:immunology / Q000378:metabolism / Q000382:microbiology; D008670:Metals / Q000378:metabolism*; D051379:Mice; D050296:Microbial Viability; D009169:Mycobacterium tuberculosis / Q000502:physiology*; D011994:Recombinant Proteins; D014376:Tuberculosis / Q000276:immunology / Q000382:microbiology*; D000069178:Type II Secretion Systems; D015032:Zinc / Q000378:metabolism
chemical_list: D001426:Bacterial Proteins; D008670:Metals; D011994:Recombinant Proteins; D000069178:Type II Secretion Systems; D007501:Iron; D015032:Zinc