title: ESX-1 and phthiocerol dimycocerosates of Mycobacterium tuberculosis act in concert to cause phagosomal rupture and host cell apoptosis.
abstract: Although phthiocerol dimycocerosates (DIM) are major virulence factors of Mycobacterium tuberculosis (Mtb), the causative agent of human tuberculosis, little is known about their mechanism of action. Localized in the outer membrane of mycobacterial pathogens, DIM are predicted to interact with host cell membranes. Interaction with eukaryotic membranes is a property shared with another virulence factor of Mtb, the early secretory antigenic target EsxA (also known as ESAT-6). This small protein, which is secreted by the type VII secretion system ESX-1 (T7SS/ESX-1), is involved in phagosomal rupture and cell death induced by virulent mycobacteria inside host phagocytes. In this work, by the use of several knock-out or knock-in mutants of Mtb or Mycobacterium bovis BCG strains and different cell biological assays, we present conclusive evidence that ESX-1 and DIM act in concert to induce phagosomal membrane damage and rupture in infected macrophages, ultimately leading to host cell apoptosis. These results identify an as yet unknown function for DIM in the infection process and open up a new research field for the study of the interaction of lipid and protein virulence factors of Mtb.
authors.affiliation: Institut de Pharmacologie et de Biologie Structurale (IPBS), CNRS-Université de Toulouse (UPS), Toulouse, France.
authors.forename: Jacques
authors.initials: J
authors.lastname: Augenstreich
authors.affiliation: Institut de Pharmacologie et de Biologie Structurale (IPBS), CNRS-Université de Toulouse (UPS), Toulouse, France.
authors.forename: Ainhoa
authors.initials: A
authors.lastname: Arbues
authors.affiliation: Unit for Integrated Mycobacterial Pathogenomics, Institut Pasteur, Paris, France.
authors.forename: Roxane
authors.initials: R
authors.lastname: Simeone
authors.affiliation: Institut de Pharmacologie et de Biologie Structurale (IPBS), CNRS-Université de Toulouse (UPS), Toulouse, France.
authors.forename: Evert
authors.initials: E
authors.lastname: Haanappel
authors.affiliation: Institut de Pharmacologie et de Biologie Structurale (IPBS), CNRS-Université de Toulouse (UPS), Toulouse, France.
authors.forename: Alice
authors.initials: A
authors.lastname: Wegener
authors.affiliation: Unit for Integrated Mycobacterial Pathogenomics, Institut Pasteur, Paris, France.
authors.forename: Fadel
authors.initials: F
authors.lastname: Sayes
authors.affiliation: Unit for Integrated Mycobacterial Pathogenomics, Institut Pasteur, Paris, France.
authors.forename: Fabien
authors.initials: F
authors.lastname: Le Chevalier
authors.affiliation: Institut de Pharmacologie et de Biologie Structurale (IPBS), CNRS-Université de Toulouse (UPS), Toulouse, France.
authors.forename: Christian
authors.initials: C
authors.lastname: Chalut
authors.affiliation: Institut de Pharmacologie et de Biologie Structurale (IPBS), CNRS-Université de Toulouse (UPS), Toulouse, France.
authors.forename: Wladimir
authors.initials: W
authors.lastname: Malaga
authors.affiliation: Institut de Pharmacologie et de Biologie Structurale (IPBS), CNRS-Université de Toulouse (UPS), Toulouse, France.
authors.forename: Christophe
authors.initials: C
authors.lastname: Guilhot
authors.affiliation: Unit for Integrated Mycobacterial Pathogenomics, Institut Pasteur, Paris, France.
authors.forename: Roland
authors.initials: R
authors.lastname: Brosch
authors.affiliation: Institut de Pharmacologie et de Biologie Structurale (IPBS), CNRS-Université de Toulouse (UPS), Toulouse, France.
authors.forename: Catherine
authors.identifier: 0000-0003-1801-8105
authors.initials: C
authors.lastname: Astarie-Dequeker
mesh_terms: D000942:Antigens, Bacterial / Q000378:metabolism*; D017209:Apoptosis / Q000502:physiology*; D001426:Bacterial Proteins / Q000378:metabolism*; D045744:Cell Line, Tumor; D002462:Cell Membrane / Q000473:pathology; D006801:Humans; D008055:Lipids / Q000502:physiology*; D008264:Macrophages / Q000378:metabolism* / Q000382:microbiology; D009163:Mycobacterium bovis / Q000472:pathogenicity*; D009169:Mycobacterium tuberculosis / Q000472:pathogenicity*; D010588:Phagosomes / Q000378:metabolism* / Q000382:microbiology; D000074084:THP-1 Cells; D037521:Virulence Factors
chemical_list: D000942:Antigens, Bacterial; D001426:Bacterial Proteins; C093276:ESAT-6 protein, Mycobacterium tuberculosis; D008055:Lipids; D037521:Virulence Factors; C008901:phthiocerol dimycocerosate
keywords: ESX-1; Mycobacterium; macrophage; phagosomal membrane rupture; phthiocerol dimycocerosates; tuberculosis