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The Mycobacterium marinum ESX-1 system mediates phagosomal permeabilization and type I interferon production via
Julia Lienard1, Esther Nobs1, Victoria Lovins1
1Department of Biology, Section for Molecular Cell Biology, Lund University, 223 62 Lund, Sweden.
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.
Insights
Mycobacterium marinum's ESX-1 secretion system disrupts host cells independently of ESAT-6. This system triggers type I interferon production by releasing host DNA into the cytosol, not through passive leakage.
Area of Science:
- Microbiology
- Immunology
- Cell Biology
Background:
- The ESX-1 secretion system of Mycobacterium tuberculosis is crucial for tuberculosis pathogenesis.
- It is known to permeabilize phagosomal membranes and induce type I interferon production.
- The current model implicates ESAT-6 in membrane permeabilization and subsequent host DNA sensing.
Purpose of the Study:
- To investigate the role of ESAT-6 in ESX-1-mediated phagosomal permeabilization and type I interferon induction.
- To elucidate the mechanisms underlying ESX-1's interaction with host cells.
- To revise the existing model of ESX-1 function in mycobacterial pathogenesis.
Main Methods:
- Utilized a collection of Mycobacterium marinum ESX-1 transposon mutants.
- Employed a macrophage infection model.
- Analyzed phagosomal membrane integrity and type I interferon production.
Main Results:
- Phagosomal membrane permeabilization by ESX-1 does not require ESAT-6 secretion.
- Loss of membrane integrity alone is insufficient to induce type I interferon production.
- Type I interferon production correlates with the release of host mitochondrial and nuclear DNA into the cytosol, requiring intact ESX-1 function.
Conclusions:
- ESX-1 affects host membrane integrity and DNA release through genetically separable mechanisms.
- The study proposes a revised model for ESX-1-mediated host interactions.
- Further research is needed to understand how ESX-1 permeabilizes host membranes and induces type I interferon responses.
