ESX‐1 and phthiocerol dimycocerosates of Mycobacterium tuberculosis act in concert to cause phagosomal rupture and host cell apoptosis

• Published in: Cellular microbiology Vol. 19; no. 7; pp. e12726 - n/a
• Main Authors: Augenstreich, Jacques, Arbues, Ainhoa, Simeone, Roxane, Haanappel, Evert, Wegener, Alice, Sayes, Fadel, Le Chevalier, Fabien, Chalut, Christian, Malaga, Wladimir, Guilhot, Christophe, Brosch, Roland, Astarie‐Dequeker, Catherine
• Format: Journal Article
• Language: English
• Published: England John Wiley & Sons, Inc 01.07.2017; Wiley
• Subjects: Antigens; Antigens, Bacterial - metabolism; Apoptosis; Apoptosis - physiology; Bacillus Calmette-Guerin vaccine; Bacterial Proteins - metabolism; BCG; Cell death; Cell Line, Tumor; Cell Membrane - pathology; Cell membranes; Cellular Biology; ESAT-6 antigen; ESX‐1; Humans; Immunology; Life Sciences; Lipids; Lipids - physiology; macrophage; Macrophages; Macrophages - metabolism; Macrophages - microbiology; Membranes; Microbiology and Parasitology; Mycobacterium; Mycobacterium bovis - pathogenicity; Mycobacterium tuberculosis - pathogenicity; Pathogens; Phagocytes; phagosomal membrane rupture; Phagosomes - metabolism; Phagosomes - microbiology; phthiocerol dimycocerosates; Proteins; Rupture; Rupturing; Secretion; THP-1 Cells; Tuberculosis; Virulence; Virulence Factors; Mycobacterium; macrophage; phagosomal membrane rupture; phthiocerol dimycocerosates; ESX-1; tuberculosis
• ISSN: 1462-5814; 1462-5822; 1462-5822
• DOI: 10.1111/cmi.12726

Summary 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. Here we demonstrate by the use of knock‐out and knock‐in bacterial mutants that two key pathogenicity determinants of Mycobacterium tuberculosis, the cell wall lipids phthiocerol dimycocerosates (abbreviated DIM or PDIM) and the type VII secretion system ESX‐1, act in concert for the induction of phagosomal membrane damage/rupture in human macrophages, ultimately leading to host cell apoptosis. As such, our data open new and exciting perspectives for better understanding the virulence mechanisms of M. tuberculosis and designing alternative intervention strategies.