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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
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 Acad Sciences
external identifiers
  • pmid:31879349
  • scopus:85077934884
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
2020-07-08 05:11:40
@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},
  language     = {eng},
  number       = {2},
  pages        = {1160--1166},
  publisher    = {National Acad 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},
}