Disconnecting<i>In Vitro</i>ESX-1 Secretion from Mycobacterial Virulence

Champion, Patricia A.

doi:10.1128/jb.01145-13

Cited by 14 publications

(12 citation statements)

References 38 publications

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“…Thus, the secretion of ESX-1 substrates in vitro, which may also include hemolysis, may not reflect the levels of secretion required to function in the environment (host, water, and soil, etc.) or to permeabilize the phagosomal membrane (91). Further experimentation is required to distinguish between these possibilities.…”

Section: Discussionmentioning

confidence: 99%

A New ESX-1 Substrate in Mycobacterium marinum That Is Required for Hemolysis but Not Host Cell Lysis

et al. 2019

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The ESX-1 (ESAT-6 system 1) secretion system plays a conserved role in the virulence of diverse mycobacterial pathogens, including the human pathogen Mycobacterium tuberculosis and M. marinum, an environmental mycobacterial species. The ESX-1 system promotes the secretion of protein virulence factors to the extracytoplasmic environment. The secretion of these proteins triggers the host response by lysing the phagosome during macrophage infection. Using proteomic analyses of the M. marinum secretome in the presence and absence of a functional ESX-1 system, we and others have hypothesized that MMAR_2894, a PE family protein, is a potential ESX-1 substrate in M. marinum. We used genetic and quantitative proteomic approaches to determine if MMAR_2894 is secreted by the ESX-1 system, and we defined the requirement of MMAR_2894 for ESX-1-mediated secretion and virulence. We show that MMAR_2894 is secreted by the ESX-1 system in M. marinum and is itself required for the optimal secretion of the known ESX-1 substrates in M. marinum. Moreover, we found that MMAR_2894 was differentially required for hemolysis and cytolysis of macrophages, two lytic activities ascribed to the M. marinum ESX-1 system. IMPORTANCE Both Mycobacterium tuberculosis, the cause of human tuberculosis (TB), and Mycobacterium marinum, a pathogen of ectotherms, use the ESX-1 secretion system to cause disease. There are many established similarities between the ESX-1 systems in M. tuberculosis and in M. marinum. Yet the two bacteria infect different hosts, hinting at species-specific functions of the ESX-1 system. Our findings demonstrate that MMAR_2894 is a PE protein secreted by the ESX-1 system of M. marinum. We show that MMAR_2894 is required for the optimal secretion of mycobacterial proteins required for disease. Because the MMAR_2894 gene is not conserved in M. tuberculosis, our findings demonstrate that MMAR_2894 may contribute to a species-specific function of the ESX-1 system in M. marinum, providing new insight into how the M. marinum and M. tuberculosis systems differ.

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Section: Discussionmentioning

confidence: 99%

A New ESX-1 Substrate in Mycobacterium marinum That Is Required for Hemolysis but Not Host Cell Lysis

et al. 2019

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“…It is likely that in the study of Chen et al (60), too little protein was analyzed to detect protein secretion by Western blot analysis. Secretion at lower than the levels of detection by Western blot analysis are sufficient to promote hemolysis and virulence (63,(79)(80)(81). The H37Rv M. tb strain is virulent despite reduced levels of ESX-1 secretion (56).…”

Section: Discussionmentioning

confidence: 99%

WhiB6 regulation of ESX-1 gene expression is controlled by a negative feedback loop inMycobacterium marinum

Bosserman

Nguyen

Sanchez

et al. 2017

Proc. Natl. Acad. Sci. U.S.A.

129

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ESX (ESAT-6 system) export systems play diverse roles across mycobacterial species. Interestingly, genetic disruption of ESX systems in different species does not result in an accumulation of protein substrates in the mycobacterial cell. However, the mechanisms underlying this observation are elusive. We hypothesized that the levels of ESX substrates were regulated by a feedback-control mechanism, linking the levels of substrates to the secretory status of ESX systems. To test this hypothesis, we used a combination of genetic, transcriptomic, and proteomic approaches to define export-dependent mechanisms regulating the levels of ESX-1 substrates in WhiB6 is a transcription factor that regulates expression of genes encoding ESX-1 substrates. We found that, in the absence of the genes encoding conserved membrane components of the ESX-1 system, the expression of the gene and genes encoding ESX-1 substrates were reduced. Accordingly, the levels of ESX-1 substrates were decreased, and WhiB6 was not detected in strains lacking genes encoding ESX-1 components. We demonstrated that, in the absence of EccCb, a conserved ESX-1 component, substrate gene expression was restored by constitutive, but not native, expression of the gene. Finally, we found that the loss of WhiB6 resulted in a virulent strain with reduced ESX-1 secretion. Together, our findings demonstrate that the levels of ESX-1 substrates in are fine-tuned by negative feedback control, linking the expression of the gene to the presence, not the functionality, of the ESX-1 membrane complex.

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“…The ESX-1 system is one of the main differentiation factors that may be determining a big percentage of the more virulent phenotype observed in the clinical isolate UT205. It has been reported that the ESX-1 secretion system can be induced by growing the mycobacteria in Sauton's medium [62][63][64]. The ESX-1 secretion system is a region that is absent in BCG, and it has been involved in virulence through proteins such as Esx-A (ESAT6) and Esx-B (CFP-10) [65].…”

Section: Main Transcriptomic Changes Between Ut127 and Ut205mentioning

confidence: 99%

Differential determinants of virulence in twoMycobacterium tuberculosisColombian clinical isolates of the LAM09 family

et al. 2019

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The heterogeneity of the clinical outcome of Mycobacterium tuberculosis (Mtb) infection may be due in part to different strategies used by circulating strains to cause disease. This heterogeneity is one of the main limitations to eradicate tuberculosis disease. In this study, we have compared the transcriptional response of two closely related Colombian clinical isolates (UT127 and UT205) of the LAM family under two axenic media conditions. These clinical isolates are phenotypically different at the level of cell death, cytokine production, growth kinetics upon in vitro infection of human tissue macrophages, and membrane vesicle secretion upon culture in synthetic medium. Using RNA-seq, we have identified different pathways that account for two different strategies to cope with the stressful condition of a carbon-poor media such as Sauton's. We showed that the clinical isolate UT205 focus mainly in the activation of virulence systems such as the ESX-1, synthesis of diacyl-trehalose, polyacyltrehalose, and sulfolipids, while UT127 concentrates its efforts mainly in the survival mode by the activation of the DNA replication, cell division, and lipid biosynthesis. This is an example of two Mtb isolates that belong to the same family and lineage, and even though they have a very similar genome, its transcriptional regulation showed important differences. This results in summary highlight the necessity to reach a better understanding of the heterogeneity in the behavior of these circulating Mtb strains which may help us to design better treatments and vaccines and to identify new targets for drugs.

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DisconnectingIn VitroESX-1 Secretion from Mycobacterial Virulence

Cited by 14 publications

References 38 publications

A New ESX-1 Substrate in Mycobacterium marinum That Is Required for Hemolysis but Not Host Cell Lysis

A New ESX-1 Substrate in Mycobacterium marinum That Is Required for Hemolysis but Not Host Cell Lysis

WhiB6 regulation of ESX-1 gene expression is controlled by a negative feedback loop inMycobacterium marinum

Differential determinants of virulence in twoMycobacterium tuberculosisColombian clinical isolates of the LAM09 family

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