Dataset Information

Modeling Tubercular ESX-1 Secretion Using Mycobacterium marinum.

ABSTRACT: Pathogenic mycobacteria cause chronic and acute diseases ranging from human tuberculosis (TB) to nontubercular infections. Mycobacterium tuberculosis causes both acute and chronic human tuberculosis. Environmentally acquired nontubercular mycobacteria (NTM) cause chronic disease in humans and animals. Not surprisingly, NTM and M. tuberculosis often use shared molecular mechanisms to survive within the host. The ESX-1 system is a specialized secretion system that is essential for virulence and is functionally conserved between M. tuberculosis and Mycobacterium marinumM. marinum is an NTM found in both salt water and freshwater that is often used to study mycobacterial virulence. Since the discovery of the secretion system in 2003, the use of both M. tuberculosis and M. marinum has defined the conserved molecular mechanisms underlying protein secretion and the lytic and regulatory activities of the ESX-1 system. Here, we review the trajectory of the field, including key discoveries regarding the ESX-1 system. We highlight the contributions of M. marinum studies and the conserved and unique aspects of the ESX-1 secretion system.

SUBMITTER: Chirakos AE

PROVIDER: S-EPMC8570393 | biostudies-literature | 2020 Nov

REPOSITORIES: biostudies-literature

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Modeling Tubercular ESX-1 Secretion Using Mycobacterium marinum.

Chirakos Alexandra E AE Balaram Ariane A Conrad William W Champion Patricia A PA

Microbiology and molecular biology reviews : MMBR 20200902 4

Pathogenic mycobacteria cause chronic and acute diseases ranging from human tuberculosis (TB) to nontubercular infections. <i>Mycobacterium tuberculosis</i> causes both acute and chronic human tuberculosis. Environmentally acquired nontubercular mycobacteria (NTM) cause chronic disease in humans and animals. Not surprisingly, NTM and <i>M. tuberculosis</i> often use shared molecular mechanisms to survive within the host. The ESX-1 system is a specialized secretion system that is essential for vi ...[more]

PMID: 32878966

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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.

Project description:The mycobacterial cell envelope is a major virulence determinant in pathogenic mycobacteria. Specific outer lipids play roles in pathogenesis, modulating the immune system and promoting the secretion of virulence factors. ESX-1 (ESAT-6 system-1) is a conserved protein secretion system required for mycobacterial pathogenesis. Previous studies revealed that mycobacterial strains lacking the outer lipid PDIM have impaired ESX-1 function during laboratory growth and infection. The mechanisms underlying changes in ESX-1 function are unknown. We used a proteo-genetic approach to measure phthiocerol dimycocerosate (PDIM)- and phenolic glycolipid (PGL)-dependent protein secretion in M. marinum, a non-tubercular mycobacterial pathogen that causes tuberculosis-like disease in ectothermic animals. Importantly, M. marinum is a well-established model for mycobacterial pathogenesis. Our findings showed that M. marinum strains without PDIM and PGL showed specific, significant reductions in protein secretion compared to the WT and complemented strains. We recently established a hierarchy for the secretion of ESX-1 substrates in four (I-IV) groups. Loss of PDIM differentially impacted secretion of Group III and IV ESX-1 substrates, which are likely the effectors of pathogenesis. Our data suggest that the altered secretion of specific ESX-1 substrates is responsible for the observed ESX-1-related effects in PDIM-deficient strains.IMPORTANCEMycobacterium tuberculosis, the cause of human tuberculosis, killed an estimated 1.3 million people in 2022. Non-tubercular mycobacterial species cause acute and chronic human infections. Understanding how these bacteria cause disease is critical. Lipids in the cell envelope are essential for mycobacteria to interact with the host and promote disease. Strains lacking outer lipids are attenuated for infection, but the reasons are unclear. Our research aims to identify a mechanism for attenuation of mycobacterial strains without the PDIM and PGL outer lipids in M. marinum. These findings will enhance our understanding of the importance of lipids in pathogenesis and how these lipids contribute to other established virulence mechanisms.

Dataset Information

Modeling Tubercular ESX-1 Secretion Using Mycobacterium marinum.

Publications

Modeling Tubercular ESX-1 Secretion Using Mycobacterium marinum.

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