ESX secretion systems: mycobacterial evolution to counter host immunity

Gröschel, Matthias I.; Sayes, Fadel; Siméone, Roxane; Majlessi, Laleh; Brosch, Roland

doi:10.1038/nrmicro.2016.131

Cited by 310 publications

(304 citation statements)

References 172 publications

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“…In line with these findings, Mtb DNA reaching the cytoplasm activates the host DNA-sensing pathway, targeting bacteria to autophagy in a process involving cGAS and the STING/TBK1/IRF3 pathway [26,27]. This pathway has been shown to activate the Type I IFN that, by promoting inflammation, may be linked to TB pathogenesis [27], which plays a critical role in dictating the clinical outcome of Mtb infection [12,28]. Indeed, mice where ATG5 has been geneti- cally inactivated are more susceptible to Mtb infection, though depletion of the PMNs using a specific antibody was able to protect these mice from the emergence of extensive tissue damage and inflammatory response in the lung [12], pointing to a key link between autophagy and inflammation.…”

Section: The Intracellular Outcomes Of Mtb Infectionmentioning

confidence: 55%

Host Directed Therapies for Tuberculosis: Futures Strategies for an Ancient Disease

Palucci

Delogu

2018

Chemotherapy

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The emergence and spread of drug-resistant strains of Mycobacterium tuberculosis is worsening the global threat of tuberculosis (TB). There is a need and urgency for the development of new treatments for TB, for the management of drug resistant TB (MDR-TB) and for improved regimens against drug-susceptible TB, with the goal of reducing toxicity and length of therapy that will boost patience compliance. The paucity of new drugs is a major obstacle to design new regimens while host-directed therapies (HDTs) are emerging as a promising area of research and are opening new avenues to fight TB. In this review, we discuss examples of potentially promising strategies aimed at improving the host response to M. tuberculosis, and argue how a better understanding of TB pathogenesis, with the fine characterization of the immunological mediators involved, may pave the way for the design of new therapies, the identification of new drugs or the repurposing of some already in use for other diseases. We emphasize that any HDTs shall be included as adjunct therapy to the drug-combination regimens already in use for TB, with the goal to reduce tissue damage and immunopathology and enhance bacterial clearance. We anticipate that the benefits of HDTs against TB will be highest against MDR-TB, where the activity of current regimens is poor and the cost high.

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Section: The Intracellular Outcomes Of Mtb Infectionmentioning

confidence: 55%

Host Directed Therapies for Tuberculosis: Futures Strategies for an Ancient Disease

Palucci

Delogu

2018

Chemotherapy

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“…As these motifs are typically present in type VII 13 substrates, this novel mechanism of substrate recognition and protein 14 translocation may be conserved across other type VII systems. 15 …”

Section: Type VII Secretion In Bacillus 12mentioning

confidence: 99%

The Enigmatic Esx Proteins: Looking Beyond Mycobacteria

Unnikrishnan

Constantinidou

Palmer

et al. 2017

Trends in Microbiology

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1Bacteria export proteins across membranes using a range of transport 2 machineries. Type VII secretion systems (T7SSs), originally described in 3 mycobacteria, are now known to be widespread across diverse bacterial 4 phyla. Recent studies have characterized secretion components and 5 mechanisms of type VII secretion in pathogenic and environmental bacteria. A 6 variety of functions have been attributed to T7SS substrates, including 7interactions with eukaryotes and with other bacteria. Here, we evaluate the 8 growing body of knowledge on T7SSs, with focus on the non-mycobacterial 9 systems, reviewing their phylogenetic distribution, structure and function in 10 diverse settings. 11 12 3

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“…There has been a decades-long search to better understand and identify the precise mechanisms by which Mtb causes disease. One virulence determinant that has been identified is a highly immunogenic secreted protein called ESAT-6 (6-kDa early secretory antigenic target) (2,3). ESAT-6 was first identified as a secreted antigen that stimulated T cells (4).…”

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confidence: 99%

Mycobacterial ESX-1 secretion system mediates host cell lysis through bacterium contact-dependent gross membrane disruptions

Conrad

Osman

Shanahan

et al. 2017

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

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228

273

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Mycobacterium tuberculosis and Mycobacterium marinum are thought to exert virulence, in part, through their ability to lyse host cell membranes. The type VII secretion system ESX-1 [6-kDa early secretory antigenic target (ESAT-6) secretion system 1] is required for both virulence and host cell membrane lysis. Both activities are attributed to the pore-forming activity of the ESX-1-secreted substrate ESAT-6 because multiple studies have reported that recombinant ESAT-6 lyses eukaryotic membranes. We too find ESX-1 of M. tuberculosis and M. marinum lyses host cell membranes. However, we find that recombinant ESAT-6 does not lyse cell membranes. The lytic activity previously attributed to ESAT-6 is due to residual detergent in the preparations. We report here that ESX-1-dependent cell membrane lysis is contact dependent and accompanied by gross membrane disruptions rather than discrete pores. ESX-1-mediated lysis is also morphologically distinct from the contact-dependent lysis of other bacterial secretion systems. Our findings suggest redirection of research to understand the mechanism of ESX-1-mediated lysis.Mycobacterium tuberculosis | Mycobacterium marinum | ESAT-6 | ESX-1 secretion system | cell membrane lysis

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ESX secretion systems: mycobacterial evolution to counter host immunity

Cited by 310 publications

References 172 publications

Host Directed Therapies for Tuberculosis: Futures Strategies for an Ancient Disease

Host Directed Therapies for Tuberculosis: Futures Strategies for an Ancient Disease

The Enigmatic Esx Proteins: Looking Beyond Mycobacteria

Mycobacterial ESX-1 secretion system mediates host cell lysis through bacterium contact-dependent gross membrane disruptions

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