The Mycobacterium marinum ESX-1 system mediates phagosomal permeabilization and type I interferon production via separable mechanisms

Research output: Contribution to journalArticle

Abstract

Following mycobacterial entry into macrophages the ESX-1 type VII secretion system promotes phagosomal permeabilization and type I IFN production, key features of tuberculosis pathogenesis. The current model states that the secreted substrate ESAT-6 is required for membrane permeabilization and that a subsequent passive leakage of extracellular bacterial DNA into the host cell cytosol is sensed by the cyclic GMP-AMP synthase (cGAS) and stimulator of IFN genes (STING) pathway to induce type I IFN production. We employed a collection of Mycobacterium marinum ESX-1 transposon mutants in a macrophage infection model and show that permeabilization of the phagosomal membrane does not require ESAT-6 secretion. Moreover, loss of membrane integrity is insufficient to induce type I IFN production. Instead, type I IFN production requires intact ESX-1 function and correlates with release of mitochondrial and nuclear host DNA into the cytosol, indicating that ESX-1 affects host membrane integrity and DNA release via genetically separable mechanisms. These results suggest a revised model for major aspects of ESX-1-mediated host interactions and put focus on elucidating the mechanisms by which ESX-1 permeabilizes host membranes and induces the type I IFN response, questions of importance for our basic understanding of mycobacterial pathogenesis and innate immune sensing.

Details

Authors
Organisations
External organisations
  • University of Pennsylvania
Research areas and keywords

Subject classification (UKÄ) – MANDATORY

  • Microbiology in the medical area
  • Microbiology

Keywords

  • ESAT-6 secretion, Membrane permeabilization, Mitochondrion, Mycobacterial pathogenesis, Type I interferon
Original languageEnglish
Pages (from-to)1160-1166
Number of pages7
JournalProceedings of the National Academy of Sciences of the United States of America
Volume117
Issue number2
Publication statusPublished - 2020
Publication categoryResearch
Peer-reviewedYes