ESX-1 and phthiocerol dimycocerosates ofMycobacterium tuberculosisact 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.

Unexpected Genomic and Phenotypic Diversity of Mycobacterium africanum Lineage 5 Affects Drug Resistance, Protein Secretion, and Immunogenicity

“…2017), which also involves a wide range of virulence lipids (Gonzalo-Asensio et al. 2014; Augenstreich et al. 2017).…”

Esx Systems and the Mycobacterial Cell Envelope: What's the Connection?

“…The same study investigated if the mycobacterial lipid PDIM enhances phago-somal lysis by the ESX-1 system by incubating EsxA with vesicles with and without PDIM. Membrane lysis was enhanced in the PDIM-containing vesicles (24). In light of the paper by Conrad et al (182), the mechanism linking PDIM to ESX-1 lysis is unlikely directly through EsxA.…”

“…Although strains bearing mutations in genes required for PDIM production are still competent to secrete ESX-1 substrates in vitro, recent studies have suggested that PDIM works synergistically with ESX-1 to promote phagosomal damage (24,25). A recent study by Quigley et al linked the levels of PDIM production with the ability of M. tuberculosis to promote phagosomal damage and downstream events in the macrophage (25).…”

“…In light of the paper by Conrad et al (182), the mechanism linking PDIM to ESX-1 lysis is unlikely directly through EsxA. Yet, both studies concluded that PDIM aids in ESX-1-mediated membrane damage by likely inserting into and changing the biophysical properties of the phagosomal membrane, making it more susceptible to lysis by the ESX-1 system (24,25).…”

Virulence Factors and Pathogenicity of Mycobacterium

“…PDIM is involved in the phagocytosis dependent of receptor through a macrophage plasma membrane reorganization mechanism [37]. Recent findings suggest that PDIM and ESAT-6 protein act together to induce phagosome membrane damage and apoptosis [38]. PGL is produced principally by fast growing mycobacteria; most of MTB isolates and H37Rv are unable to produce it, phenomenon caused by a mutation in the phs15/1 gene.…”