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

Lienard, Julia LU ; Nobs, Esther LU ; Lovins, Victoria LU ; Movert, Elin LU ; Valfridsson, Christine LU and Carlsson, Fredric LU (2020) In Proceedings of the National Academy of Sciences of the United States of America 117(2). p.1160-1166
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... (More)

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.

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author
; ; ; ; and
organization
publishing date
type
Contribution to journal
publication status
published
subject
keywords
ESAT-6 secretion, Membrane permeabilization, Mitochondrion, Mycobacterial pathogenesis, Type I interferon
in
Proceedings of the National Academy of Sciences of the United States of America
volume
117
issue
2
pages
7 pages
publisher
National Academy of Sciences
external identifiers
  • scopus:85077934884
  • pmid:31879349
ISSN
0027-8424
DOI
10.1073/pnas.1911646117
language
English
LU publication?
yes
id
0e839e55-a2ce-4d5e-bc20-71872f92222d
date added to LUP
2020-02-03 10:40:32
date last changed
2024-04-17 02:43:45
@article{0e839e55-a2ce-4d5e-bc20-71872f92222d,
  abstract     = {{<p>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.</p>}},
  author       = {{Lienard, Julia and Nobs, Esther and Lovins, Victoria and Movert, Elin and Valfridsson, Christine and Carlsson, Fredric}},
  issn         = {{0027-8424}},
  keywords     = {{ESAT-6 secretion; Membrane permeabilization; Mitochondrion; Mycobacterial pathogenesis; Type I interferon}},
  language     = {{eng}},
  number       = {{2}},
  pages        = {{1160--1166}},
  publisher    = {{National Academy of Sciences}},
  series       = {{Proceedings of the National Academy of Sciences of the United States of America}},
  title        = {{The Mycobacterium marinum ESX-1 system mediates phagosomal permeabilization and type I interferon production via separable mechanisms}},
  url          = {{http://dx.doi.org/10.1073/pnas.1911646117}},
  doi          = {{10.1073/pnas.1911646117}},
  volume       = {{117}},
  year         = {{2020}},
}