Mycobacterium tuberculosis EsxH inhibits ESCRT-dependent CD4+ T-cell activation

Portal-Celhay, Cynthia; Tufariello, Jo Ann M.; Srivastava, Smita; Zahra, Aleena; Klevorn, Thaís; Grace, Patricia S.; Mehra, Alka; Park, Heidi S.; Ernst, Joel D.; Jacobs, William R.; Philips, Jennifer A.

doi:10.1038/nmicrobiol.2016.232

Cited by 84 publications

(75 citation statements)

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“…The ESX-1 system is functionally conserved between M. tuberculosis, the cause of human tuberculosis, and Mycobacterium marinum, a pathogen of poikilothermic fish and an established model for the ESX-1 system (14)(15)(16)(17)(18). Phagosomal lysis releases secreted bacterial factors and triggers the host response to infection (7,8,(19)(20)(21)(22)(23)(24)(25)(26)(27). In the absence of an ESX-1 system, both mycobacterial pathogens remain in the phagosome and are attenuated (7)(8)(9)22).…”

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confidence: 99%

EspM Is a Conserved Transcription Factor That Regulates Gene Expression in Response to the ESX-1 System

Sanchez

Ferrell

Chirakos

et al. 2020

mBio

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Pathogenic mycobacteria encounter multiple environments during macrophage infection. Temporally, the bacteria are engulfed into the phagosome, lyse the phagosomal membrane, and interact with the cytosol before spreading to another cell. Virulence factors secreted by the mycobacterial ESX-1 (ESAT-6-system-1) secretion system mediate the essential transition from the phagosome to the cytosol. It was recently discovered that the ESX-1 system also regulates mycobacterial gene expression in Mycobacterium marinum (R. E. Bosserman, T. T. Nguyen, K. G. Sanchez, A. E. Chirakos, et al., Proc Natl Acad Sci U S A 114:E10772–E10781, 2017, https://doi.org/10.1073/pnas.1710167114), a nontuberculous mycobacterial pathogen, and in the human-pathogenic species M. tuberculosis (A. M. Abdallah, E. M. Weerdenburg, Q. Guan, R. Ummels, et al., PLoS One 14:e0211003, 2019, https://doi.org/10.1371/journal.pone.0211003). It is not known how the ESX-1 system regulates gene expression. Here, we identify the first transcription factor required for the ESX-1-dependent transcriptional response in pathogenic mycobacteria. We demonstrate that the gene divergently transcribed from the whiB6 gene and adjacent to the ESX-1 locus in mycobacterial pathogens encodes a conserved transcription factor (MMAR_5438, Rv3863, now espM). We prove that EspM from both M. marinum and M. tuberculosis directly and specifically binds the whiB6-espM intergenic region. We show that EspM is required for ESX-1-dependent repression of whiB6 expression and for the regulation of ESX-1-associated gene expression. Finally, we demonstrate that EspM functions to fine-tune ESX-1 activity in M. marinum. Taking the data together, this report extends the esx-1 locus, defines a conserved regulator of the ESX-1 virulence pathway, and begins to elucidate how the ESX-1 system regulates gene expression. IMPORTANCE Mycobacterial pathogens use the ESX-1 system to transport protein substrates that mediate essential interactions with the host during infection. We previously demonstrated that in addition to transporting proteins, the ESX-1 secretion system regulates gene expression. Here, we identify a conserved transcription factor that regulates gene expression in response to the ESX-1 system. We demonstrate that this transcription factor is functionally conserved in M. marinum, a pathogen of ectothermic animals; M. tuberculosis, the human-pathogenic species that causes tuberculosis; and M. smegmatis, a nonpathogenic mycobacterial species. These findings provide the first mechanistic insight into how the ESX-1 system elicits a transcriptional response, a function of this protein transport system that was previously unknown.

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confidence: 99%

EspM Is a Conserved Transcription Factor That Regulates Gene Expression in Response to the ESX-1 System

Sanchez

Ferrell

Chirakos

et al. 2020

mBio

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“…We also found that multiple members of the ESAT-6 family proteins were upregulated upon resuscitation (Harboe et al, 1996;Priscille et al, 2004), including EsxA (Sandra et al, 2010;Zhang et al, 2016), EsxB (Sandra et al, 2010), EsxG (Sweeney et al, 2011), EsxH (Alka et al, 2013;Portal-Celhay et al, 2016), EsxK, and EsxN (Zhigang et al, 2017). These proteins are components of the Type VII secretion systems, and many of them are important T cell antigens and play a critical role modulating the host-pathogen interactions (Abdallah et al, 2007).…”

Section: Discussionmentioning

confidence: 94%

Transcriptome Changes of Mycobacterium marinum in the Process of Resuscitation From Hypoxia-Induced Dormancy

et al. 2020

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Nearly one-third of the world's population is latently infected with Mycobacterium tuberculosis (M. tb), which represents a huge disease reservoir for reactivation and a major obstacle for effective control of tuberculosis. During latent infection, M. tb is thought to enter nonreplicative dormant states by virtue of its response to hypoxia and nutrientdeprived conditions. Knowledge of the genetic programs used to facilitate entry into and exit from the nonreplicative dormant states remains incomplete. In this study, we examined the transcriptional changes of Mycobacterium marinum (M. marinum), a pathogenic mycobacterial species closely related to M. tb, at different stages of resuscitation from hypoxia-induced dormancy. RNA-seq analyses were performed on M. marinum cultures recovered at multiple time points after resuscitation. Differentially expressed genes (DEGs) at each time period were identified and analyzed. Co-expression networks of transcription factors and DEGs in each period were constructed. In addition, we performed a weighted gene co-expression network analysis (WGCNA) on all genes and obtained 12 distinct gene modules. Collectively, these data provided valuable insight into the transcriptome changes of M. marinum upon resuscitation as well as gene module function of the bacteria during active metabolism and growth.

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“…ESX-3 proteins: EsxG and EsxH are associated with the (proline-glutamic acid, proline-proline-glutamic acid) PE and PPE secretion [52]. The EsxG and EsxH heterodimer, which harms macrophage phagosome maturation, is secreted by the ESX-3 system [53] and inhibits the endosomal-sorting complex required for transport (ESCRT) impairing MTB antigen-specific CD4 + activation by macrophages and DC [54]. In M. abscessus ESX3 is composed by the genes esxH, esxG, esx-3, EsxG and EsxG proteins are related with enhancement of inflammatory cytokine generation in macrophages, M. abcessus esx3 mutant resulted in less inflammatory response [55].…”

Section: Esx-3mentioning

confidence: 99%

Virulence Factors and Pathogenicity of Mycobacterium

Echeverría-Valencia¹,

Flores-Villalva²,

Espitia³

2018

Mycobacterium - Research and Development

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Virulence, is referred as the ability of a pathogen to cause disease, and for mycobacteria it depends on their ability to reside within host cells and evade the microbicidal mechanisms of macrophages. The outcome of tuberculosis (TB) infection is highly variable and it seems that the closest relationship between the Mycobacterium genre and humans has shaped the mycobacterial genome to encode bacterial factors that reflects a highly evolved and coordinated program of immune evasion strategies that interfere with both innate and adaptive immunity causing disease even in fully immunocompetent host. Although Mycobacterium tuberculosis (MTB) does not have classical virulence factors, it has described many virulence-associated genes and virulence lifestyle genes from Mycobacterium tuberculosis complex (MTBC). In this chapter, we describe the most important gene/molecule involved in the host defense modulation response, also the plethora of strategies to evade immune mechanisms of macrophage. We review the main genes whose inactivation in the mycobacterial genome leads to a measurable loss in virulence in the different validated TB models.

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Mycobacterium tuberculosis EsxH inhibits ESCRT-dependent CD4+ T-cell activation

Cited by 84 publications

References 50 publications

EspM Is a Conserved Transcription Factor That Regulates Gene Expression in Response to the ESX-1 System

EspM Is a Conserved Transcription Factor That Regulates Gene Expression in Response to the ESX-1 System

Transcriptome Changes of Mycobacterium marinum in the Process of Resuscitation From Hypoxia-Induced Dormancy

Virulence Factors and Pathogenicity of Mycobacterium

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