ESX-1 and phthiocerol dimycocerosates ofMycobacterium tuberculosisact in concert to cause phagosomal rupture and host cell apoptosis

• DOI: 10.1111/cmi.12726
• Publication Date: 2017-01-17T21:23:05Z
• Authors: Jacques Augenstreich; Ainhoa Arbues; Roxane Simeone; Evert Haanappel; Alice Wegener; Fadel Sayes; Fabien Le Chevalier; Christian Chalut; Wladimir Malaga; Christophe Guilhot; Roland Brosch; Catherine Astarie...
• Keywords: 0301 basic medicine; [SDV.IMM] Life Sciences [q-bio]/Immunology; ESX-1; THP-1 Cells; Virulence Factors; [SDV]Life Sciences [q-bio]; Apoptosis; [SDV.BC]Life Sciences [q-bio]/Cellular Biology; macrophage; Mycobacterium; 03 medical and health sciences; phthiocerol dimycocerosates; Bacterial Proteins; Cell Line, Tumor; Phagosomes; Humans; [SDV.BC] Life Sciences [q-bio]/Cellular Biology; [SDV.MP] Life Sciences [q-bio]/Microbiology and Parasitology; Antigens, Bacterial; Macrophages; Cell Membrane; Mycobacterium tuberculosis; Lipids; Mycobacterium bovis; 3. Good health; [SDV] Life Sciences [q-bio]; [SDV.MP]Life Sciences [q-bio]/Microbiology and Parasitology; tuberculosis; [SDV.IMM]Life Sciences [q-bio]/Immunology; phagosomal membrane rupture

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.