The Mycobacterium marinum ESX-1 system mediates phagosomal permeabilization and type I interferon production via separable mechanisms
(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.
(Less)
- author
- Lienard, Julia LU ; Nobs, Esther LU ; Lovins, Victoria LU ; Movert, Elin LU ; Valfridsson, Christine LU and Carlsson, Fredric LU
- organization
- publishing date
- 2020
- 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
- 2024-09-19 16:21:06
@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}}, }