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

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.

SUBMITTER: Lienard J

PROVIDER: S-EPMC6969537 | biostudies-literature | 2020 Jan

REPOSITORIES: biostudies-literature

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The <i>Mycobacterium marinum</i> ESX-1 system mediates phagosomal permeabilization and type I interferon production via separable mechanisms.

Lienard Julia J Nobs Esther E Lovins Victoria V Movert Elin E Valfridsson Christine C Carlsson Fredric F

Proceedings of the National Academy of Sciences of the United States of America 20191226 2

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 ...[more]

PMID: 31879349

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Project description:Mycobacterium marinum is a nontuberculous pathogen of poikilothermic fish and an opportunistic human pathogen. Like tuberculous mycobacteria, the M. marinum M strain requires the ESX-1 (ESAT-6 system 1) secretion system for virulence in host cells. EsxB and EsxA, two major virulence factors exported by the ESX-1 system, are encoded by the esxBA genes within the ESX-1 locus. Deletion of the esxBA genes abrogates ESX-1 export and attenuates M. marinum in ex vivo and in vivo models of infection. Interestingly, there are several duplications of the esxB and esxA genes (esxB_1, esxB_2, esxA_1, esxA_2, and esxA_3) in the M. marinum M genome located outside the ESX-1 locus. We sought to understand if this region, known as ESX-6, contributes to ESX-1-mediated virulence. We found that deletion of the esxB_1 gene alone or the entire ESX-6 locus did not impact ESX-1 export or function, supporting the idea that the esxBA genes present at the ESX-1 locus are the primary contributors to ESX-1-mediated virulence. Nevertheless, overexpression of the esxB_1 locus complemented ESX-1 function in the ΔesxBA strain, signifying that the two loci are functionally equivalent. Our findings raise questions about why duplicate versions of the esxBA genes are maintained in the M. marinum M genome and how these proteins, which are functionally equivalent to virulence factors, contribute to mycobacterial biology.IMPORTANCEMycobacterium tuberculosis is the causative agent of the human disease tuberculosis (TB). There are 10.4 million cases and 1.7 million TB-associated deaths annually, making TB a leading cause of death globally. Nontuberculous mycobacteria (NTM) cause chronic human infections that are acquired from the environment. Despite differences in disease etiology, both tuberculous and NTM pathogens use the ESX-1 secretion system to cause disease. The nontubercular mycobacterial species, Mycobacterium marinum, has additional copies of specific ESX-1 genes. Our findings demonstrate that the duplicated genes do not contribute to virulence but can substitute for virulence factors in M. marinum These findings suggest that the duplicated genes may play a specific role in NTM biology.

Dataset Information

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

Publications

The <i>Mycobacterium marinum</i> ESX-1 system mediates phagosomal permeabilization and type I interferon production via separable mechanisms.

Similar Datasets

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