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ESX/Type VII Secretion Systems—An Important Way Out for Mycobacterial Proteins

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  • Authors: Farzam Vaziri1,2,3, Roland Brosch4
  • Editors: Maria Sandkvist5, Eric Cascales6, Peter J. Christie7
    Affiliations: 1: Institut Pasteur, Unit for Integrated Mycobacterial Pathogenomics, UMR3525 CNRS, 75015 Paris, France; 2: Department of Mycobacteriology and Pulmonary Research, Pasteur Institute of Iran, 13164 Tehran, Iran; 3: Microbiology Research Center, Pasteur Institute of Iran, 13164 Tehran, Iran; 4: Institut Pasteur, Unit for Integrated Mycobacterial Pathogenomics, UMR3525 CNRS, 75015 Paris, France; 5: Department of Microbiology and Immunology, University of Michigan, Ann Arbor, Michigan; 6: CNRS Aix-Marseille Université, Mediterranean Institute of Microbiology, Marseille, France; 7: Department of Microbiology and Molecular Genetics, McGovern Medical School, Houston, Texas
  • Source: microbiolspec July 2019 vol. 7 no. 4 doi:10.1128/microbiolspec.PSIB-0029-2019
  • Received 21 March 2019 Accepted 30 May 2019 Published 12 July 2019
  • Roland Brosch, [email protected]
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  • Abstract:

    The causative agent of human tuberculosis, , has a complex lipid-rich diderm envelope, which acts as a major barrier protecting the bacterium against the hostile environment inside the host cells. For the transfer of diverse molecules across this complex cell envelope, has a series of general and specialized protein secretion systems, characterized by the SecA general secretion pathway, the twin-arginine translocation pathway, and five specific ESX type VII secretion systems. In this review, we focus on the latter systems, known as ESX-1 to ESX-5, which were first discovered almost 20 years ago during the analysis of the genome sequence of H37Rv. Since then, these systems have been the subject of highly dynamic research due to their involvement in several key biological processes and host-pathogen interactions of the tubercle bacilli.

  • Citation: Vaziri F, Brosch R. 2019. ESX/Type VII Secretion Systems—An Important Way Out for Mycobacterial Proteins. Microbiol Spectrum 7(4):PSIB-0029-2019. doi:10.1128/microbiolspec.PSIB-0029-2019.


1. Hug LA, Baker BJ, Anantharaman K, Brown CT, Probst AJ, Castelle CJ, Butterfield CN, Hernsdorf AW, Amano Y, Ise K, Suzuki Y, Dudek N, Relman DA, Finstad KM, Amundson R, Thomas BC, Banfield JF. 2016. A new view of the tree of life. Nat Microbiol 1:16048. http://dx.doi.org/10.1038/nmicrobiol.2016.48. [PubMed]
2. Chagnot C, Zorgani MA, Astruc T, Desvaux M. 2013. Proteinaceous determinants of surface colonization in bacteria: bacterial adhesion and biofilm formation from a protein secretion perspective. Front Microbiol 4:303. http://dx.doi.org/10.3389/fmicb.2013.00303. [PubMed]
3. Gerlach RG, Hensel M. 2007. Protein secretion systems and adhesins: the molecular armory of Gram-negative pathogens. Int J Med Microbiol 297:401–415. http://dx.doi.org/10.1016/j.ijmm.2007.03.017. [PubMed]
4. Green ER, Mecsas J. 2016. Bacterial secretion systems: an overview. Microbiol Spectr 4:VMBF-0012-2015. 10.1128/microbiolspec.VMBF-0012-2015.
5. Veith PD, Glew MD, Gorasia DG, Reynolds EC. 2017. Type IX secretion: the generation of bacterial cell surface coatings involved in virulence, gliding motility and the degradation of complex biopolymers. Mol Microbiol 106:35–53. http://dx.doi.org/10.1111/mmi.13752. [PubMed]
6. Sørensen AL, Nagai S, Houen G, Andersen P, Andersen AB. 1995. Purification and characterization of a low-molecular-mass T-cell antigen secreted by Mycobacterium tuberculosis. Infect Immun 63:1710–1717.
7. Brodin P, Rosenkrands I, Andersen P, Cole ST, Brosch R. 2004. ESAT-6 proteins: protective antigens and virulence factors? Trends Microbiol 12:500–508. http://dx.doi.org/10.1016/j.tim.2004.09.007. [PubMed]
8. Abdallah AM, Gey van Pittius NC, Champion PA, Cox J, Luirink J, Vandenbroucke-Grauls CM, Appelmelk BJ, Bitter W. 2007. Type VII secretion—mycobacteria show the way. Nat Rev Microbiol 5:883–891. http://dx.doi.org/10.1038/nrmicro1773. [PubMed]
9. Houben EN, Bestebroer J, Ummels R, Wilson L, Piersma SR, Jiménez CR, Ottenhoff TH, Luirink J, Bitter W. 2012. Composition of the type VII secretion system membrane complex. Mol Microbiol 86:472–484. http://dx.doi.org/10.1111/j.1365-2958.2012.08206.x. [PubMed]
10. Beckham KS, Ciccarelli L, Bunduc CM, Mertens HD, Ummels R, Lugmayr W, Mayr J, Rettel M, Savitski MM, Svergun DI, Bitter W, Wilmanns M, Marlovits TC, Parret AH, Houben EN. 2017. Structure of the mycobacterial ESX-5 type VII secretion system membrane complex by single-particle analysis. Nat Microbiol 2:17047. http://dx.doi.org/10.1038/nmicrobiol.2017.47. [PubMed]
11. Gröschel MI, Sayes F, Simeone R, Majlessi L, Brosch R. 2016. ESX secretion systems: mycobacterial evolution to counter host immunity. Nat Rev Microbiol 14:677–691. http://dx.doi.org/10.1038/nrmicro.2016.131. [PubMed]
12. Zuber B, Chami M, Houssin C, Dubochet J, Griffiths G, Daffé M. 2008. Direct visualization of the outer membrane of mycobacteria and corynebacteria in their native state. J Bacteriol 190:5672–5680. http://dx.doi.org/10.1128/JB.01919-07. [PubMed]
13. Kaur D, Guerin ME, Skovierová H, Brennan PJ, Jackson M. 2009. Chapter 2: biogenesis of the cell wall and other glycoconjugates of Mycobacterium tuberculosis. Adv Appl Microbiol 69:23–78. http://dx.doi.org/10.1016/S0065-2164(09)69002-X.
14. Daffé M. 2015. The cell envelope of tubercle bacilli. Tuberculosis (Edinb) 95(Suppl 1) :S155–S158. http://dx.doi.org/10.1016/j.tube.2015.02.024. [PubMed]
15. Touchette MH, Seeliger JC. 2017. Transport of outer membrane lipids in mycobacteria. Biochim Biophys Acta Mol Cell Biol Lipids 1862:1340–1354. http://dx.doi.org/10.1016/j.bbalip.2017.01.005. [PubMed]
16. Bitter W, Houben EN, Bottai D, Brodin P, Brown EJ, Cox JS, Derbyshire K, Fortune SM, Gao LY, Liu J, Gey van Pittius NC, Pym AS, Rubin EJ, Sherman DR, Cole ST, Brosch R. 2009. Systematic genetic nomenclature for type VII secretion systems. PLoS Pathog 5:e1000507. http://dx.doi.org/10.1371/journal.ppat.1000507. [PubMed]
17. Cole ST, Brosch R, Parkhill J, Garnier T, Churcher C, Harris D, Gordon SV, Eiglmeier K, Gas S, Barry CE, III, Tekaia F, Badcock K, Basham D, Brown D, Chillingworth T, Connor R, Davies R, Devlin K, Feltwell T, Gentles S, Hamlin N, Holroyd S, Hornsby T, Jagels K, Krogh A, McLean J, Moule S, Murphy L, Oliver K, Osborne J, Quail MA, Rajandream MA, Rogers J, Rutter S, Seeger K, Skelton J, Squares R, Squares S, Sulston JE, Taylor K, Whitehead S, Barrell BG. 1998. Deciphering the biology of Mycobacterium tuberculosis from the complete genome sequence. Nature 393:537–544. http://dx.doi.org/10.1038/31159. [PubMed]
18. Tekaia F, Gordon SV, Garnier T, Brosch R, Barrell BG, Cole ST. 1999. Analysis of the proteome of Mycobacterium tuberculosis in silico. Tuber Lung Dis 79:329–342. http://dx.doi.org/10.1054/tuld.1999.0220. [PubMed]
19. Unnikrishnan M, Constantinidou C, Palmer T, Pallen MJ. 2017. The enigmatic Esx proteins: looking beyond mycobacteria. Trends Microbiol 25:192–204. http://dx.doi.org/10.1016/j.tim.2016.11.004. [PubMed]
20. Pallen MJ. 2002. The ESAT-6/WXG100 superfamily—and a new Gram-positive secretion system? Trends Microbiol 10:209–212. http://dx.doi.org/10.1016/S0966-842X(02)02345-4.
21. Dumas E, Christina Boritsch E, Vandenbogaert M, Rodríguez de la Vega RC, Thiberge JM, Caro V, Gaillard JL, Heym B, Girard-Misguich F, Brosch R, Sapriel G. 2016. Mycobacterial pan-genome analysis suggests important role of plasmids in the radiation of type VII secretion systems. Genome Biol Evol 8:387–402. http://dx.doi.org/10.1093/gbe/evw001. [PubMed]
22. Newton-Foot M, Warren RM, Sampson SL, van Helden PD, Gey van Pittius NC. 2016. The plasmid-mediated evolution of the mycobacterial ESX (type VII) secretion systems. BMC Evol Biol 16:62. http://dx.doi.org/10.1186/s12862-016-0631-2. [PubMed]
23. Ummels R, Abdallah AM, Kuiper V, Aâjoud A, Sparrius M, Naeem R, Spaink HP, van Soolingen D, Pain A, Bitter W. 2014. Identification of a novel conjugative plasmid in mycobacteria that requires both type IV and type VII secretion. mBio 5:e01744-14. http://dx.doi.org/10.1128/mBio.01744-14. [PubMed]
24. Stoop EJ, Bitter W, van der Sar AM. 2012. Tubercle bacilli rely on a type VII army for pathogenicity. Trends Microbiol 20:477–484. http://dx.doi.org/10.1016/j.tim.2012.07.001. [PubMed]
25. Queval CJ, Brosch R, Simeone R. 2017. The macrophage: a disputed fortress in the battle against Mycobacterium tuberculosis. Front Microbiol 8:2284. http://dx.doi.org/10.3389/fmicb.2017.02284. [PubMed]
26. Majlessi L, Prados-Rosales R, Casadevall A, Brosch R. 2015. Release of mycobacterial antigens. Immunol Rev 264:25–45. http://dx.doi.org/10.1111/imr.12251. [PubMed]
27. Ates LS, Houben EN, Bitter W. 2016. Type VII secretion: a highly versatile secretion system. Microbiol Spectr 4:VMBF-0011-2015. 10.1128/microbiolspec.VMBF-0011-2015.
28. Madacki J, Mas Fiol G, Brosch R. 2019. Update on the virulence factors of the obligate pathogen Mycobacterium tuberculosis and related tuberculosis-causing mycobacteria. Infect Genet Evol 72:67–77. http://dx.doi.org/10.1016/j.meegid.2018.12.013. [PubMed]
29. Serafini A, Boldrin F, Palù G, Manganelli R. 2009. Characterization of a Mycobacterium tuberculosis ESX-3 conditional mutant: essentiality and rescue by iron and zinc. J Bacteriol 191:6340–6344. http://dx.doi.org/10.1128/JB.00756-09. [PubMed]
30. Siegrist MS, Steigedal M, Ahmad R, Mehra A, Dragset MS, Schuster BM, Philips JA, Carr SA, Rubin EJ. 2014. Mycobacterial Esx-3 requires multiple components for iron acquisition. mBio 5:e01073-14. http://dx.doi.org/10.1128/mBio.01073-14. [PubMed]
31. Tufariello JM, Chapman JR, Kerantzas CA, Wong KW, Vilchèze C, Jones CM, Cole LE, Tinaztepe E, Thompson V, Fenyö D, Niederweis M, Ueberheide B, Philips JA, Jacobs WR, Jr. 2016. Separable roles for Mycobacterium tuberculosis ESX-3 effectors in iron acquisition and virulence. Proc Natl Acad Sci U S A 113:E348–E357. http://dx.doi.org/10.1073/pnas.1523321113. [PubMed]
32. Bottai D, Di Luca M, Majlessi L, Frigui W, Simeone R, Sayes F, Bitter W, Brennan MJ, Leclerc C, Batoni G, Campa M, Brosch R, Esin S. 2012. Disruption of the ESX-5 system of Mycobacterium tuberculosis causes loss of PPE protein secretion, reduction of cell wall integrity and strong attenuation. Mol Microbiol 83:1195–1209. http://dx.doi.org/10.1111/j.1365-2958.2012.08001.x. [PubMed]
33. Ates LS, Ummels R, Commandeur S, van de Weerd R, Sparrius M, Weerdenburg E, Alber M, Kalscheuer R, Piersma SR, Abdallah AM, Abd El Ghany M, Abdel-Haleem AM, Pain A, Jiménez CR, Bitter W, Houben EN. 2015. Essential role of the ESX-5 secretion system in outer membrane permeability of pathogenic mycobacteria. PLoS Genet 11:e1005190. http://dx.doi.org/10.1371/journal.pgen.1005190. [PubMed]
34. Gey van Pittius NC, Sampson SL, Lee H, Kim Y, van Helden PD, Warren RM. 2006. Evolution and expansion of the Mycobacterium tuberculosis PE and PPE multigene families and their association with the duplication of the ESAT-6 (esx) gene cluster regions. BMC Evol Biol 6:95. http://dx.doi.org/10.1186/1471-2148-6-95. [PubMed]
35. Bottai D, Brosch R. 2009. Mycobacterial PE, PPE and ESX clusters: novel insights into the secretion of these most unusual protein families. Mol Microbiol 73:325–328. http://dx.doi.org/10.1111/j.1365-2958.2009.06784.x. [PubMed]
36. Sayes F, Sun L, Di Luca M, Simeone R, Degaiffier N, Fiette L, Esin S, Brosch R, Bottai D, Leclerc C, Majlessi L. 2012. Strong immunogenicity and cross-reactivity of Mycobacterium tuberculosis ESX-5 type VII secretion: encoded PE-PPE proteins predicts vaccine potential. Cell Host Microbe 11:352–363. http://dx.doi.org/10.1016/j.chom.2012.03.003. [PubMed]
37. Fishbein S, van Wyk N, Warren RM, Sampson SL. 2015. Phylogeny to function: PE/PPE protein evolution and impact on Mycobacterium tuberculosis pathogenicity. Mol Microbiol 96:901–916. http://dx.doi.org/10.1111/mmi.12981. [PubMed]
38. Ates LS, Dippenaar A, Ummels R, Piersma SR, van der Woude AD, van der Kuij K, Le Chevalier F, Mata-Espinosa D, Barrios-Payán J, Marquina-Castillo B, Guapillo C, Jiménez CR, Pain A, Houben ENG, Warren RM, Brosch R, Hernández-Pando R, Bitter W. 2018. Mutations in ppe38 block PE_PGRS secretion and increase virulence of Mycobacterium tuberculosis. Nat Microbiol 3:181–188. http://dx.doi.org/10.1038/s41564-017-0090-6. [PubMed]
39. Ates LS, Dippenaar A, Sayes F, Pawlik A, Bouchier C, Ma L, Warren RM, Sougakoff W, Majlessi L, van Heijst JWJ, Brossier F, Brosch R. 2018. Unexpected genomic and phenotypic diversity of Mycobacterium africanum lineage 5 affects drug resistance, protein secretion, and immunogenicity. Genome Biol Evol 10:1858–1874. http://dx.doi.org/10.1093/gbe/evy145. [PubMed]
40. Rosenberg OS, Dovala D, Li X, Connolly L, Bendebury A, Finer-Moore J, Holton J, Cheng Y, Stroud RM, Cox JS. 2015. Substrates control multimerization and activation of the multi-domain ATPase motor of type VII secretion. Cell 161:501–512. http://dx.doi.org/10.1016/j.cell.2015.03.040. [PubMed]
41. van Winden VJC, Damen MPM, Ummels R, Bitter W, Houben ENG. 2019. Protease domain and transmembrane domain of the type VII secretion mycosin protease determine system-specific functioning in mycobacteria. J Biol Chem 294:4806–4814. http://dx.doi.org/10.1074/jbc.RA118.007090. [PubMed]
42. Bosserman RE, Champion PA. 2017. Esx systems and the mycobacterial cell envelope: what’s the connection? J Bacteriol 199:e00131-17. http://dx.doi.org/10.1128/JB.00131-17. [PubMed]
43. van Winden VJ, Ummels R, Piersma SR, Jiménez CR, Korotkov KV, Bitter W, Houben EN. 2016. Mycosins are required for the stabilization of the ESX-1 and ESX-5 type VII secretion membrane complexes. mBio 7:01471-16. http://dx.doi.org/10.1128/mBio.01471-16. [PubMed]
44. Fortune SM, Jaeger A, Sarracino DA, Chase MR, Sassetti CM, Sherman DR, Bloom BR, Rubin EJ. 2005. Mutually dependent secretion of proteins required for mycobacterial virulence. Proc Natl Acad Sci U S A 102:10676–10681. http://dx.doi.org/10.1073/pnas.0504922102. [PubMed]
45. MacGurn JA, Raghavan S, Stanley SA, Cox JS. 2005. A non-RD1 gene cluster is required for Snm secretion in Mycobacterium tuberculosis. Mol Microbiol 57:1653–1663. http://dx.doi.org/10.1111/j.1365-2958.2005.04800.x. [PubMed]
46. Chen JM. 2016. Mycosins of the mycobacterial type VII ESX secretion system: the glue that holds the party together. mBio 7:02062-16. http://dx.doi.org/10.1128/mBio.02062-16. [PubMed]
47. Lou Y, Rybniker J, Sala C, Cole ST. 2017. EspC forms a filamentous structure in the cell envelope of Mycobacterium tuberculosis and impacts ESX-1 secretion. Mol Microbiol 103:26–38. http://dx.doi.org/10.1111/mmi.13575. [PubMed]
48. Phan TH, Houben ENG. 2018. Bacterial secretion chaperones: the mycobacterial type VII case. FEMS Microbiol Lett 365:fny197. http://dx.doi.org/10.1093/femsle/fny197.
49. Phan TH, Ummels R, Bitter W, Houben EN. 2017. Identification of a substrate domain that determines system specificity in mycobacterial type VII secretion systems. Sci Rep 7:42704. http://dx.doi.org/10.1038/srep42704. [PubMed]
50. Sala C, Odermatt NT, Soler-Arnedo P, Gülen MF, von Schultz S, Benjak A, Cole ST. 2018. EspL is essential for virulence and stabilizes EspE, EspF and EspH levels in Mycobacterium tuberculosis. PLoS Pathog 14:e1007491. http://dx.doi.org/10.1371/journal.ppat.1007491. [PubMed]
51. Coros A, Callahan B, Battaglioli E, Derbyshire KM. 2008. The specialized secretory apparatus ESX-1 is essential for DNA transfer in Mycobacterium smegmatis. Mol Microbiol 69:794–808. http://dx.doi.org/10.1111/j.1365-2958.2008.06299.x. [PubMed]
52. Derbyshire KM, Gray TA. 2014. Distributive conjugal transfer: new insights into horizontal gene transfer and genetic exchange in mycobacteria. Microbiol Spectr 2:MGM2-0022-2013. http://dx.doi.org/10.1128/microbiolspec.MGM2-0022-2013.
53. Gray TA, Clark RR, Boucher N, Lapierre P, Smith C, Derbyshire KM. 2016. Intercellular communication and conjugation are mediated by ESX secretion systems in mycobacteria. Science 354:347–350. http://dx.doi.org/10.1126/science.aag0828. [PubMed]
54. Clark RR, Judd J, Lasek-Nesselquist E, Montgomery SA, Hoffmann JG, Derbyshire KM, Gray TA. 2018. Direct cell-cell contact activates SigM to express the ESX-4 secretion system in Mycobacterium smegmatis. Proc Natl Acad Sci U S A 115:E6595–E6603. http://dx.doi.org/10.1073/pnas.1804227115. [PubMed]
55. Boritsch EC, Khanna V, Pawlik A, Honoré N, Navas VH, Ma L, Bouchier C, Seemann T, Supply P, Stinear TP, Brosch R. 2016. Key experimental evidence of chromosomal DNA transfer among selected tuberculosis-causing mycobacteria. Proc Natl Acad Sci U S A 113:9876–9881. http://dx.doi.org/10.1073/pnas.1604921113. [PubMed]
56. Supply P, Marceau M, Mangenot S, Roche D, Rouanet C, Khanna V, Majlessi L, Criscuolo A, Tap J, Pawlik A, Fiette L, Orgeur M, Fabre M, Parmentier C, Frigui W, Simeone R, Boritsch EC, Debrie AS, Willery E, Walker D, Quail MA, Ma L, Bouchier C, Salvignol G, Sayes F, Cascioferro A, Seemann T, Barbe V, Locht C, Gutierrez MC, Leclerc C, Bentley SD, Stinear TP, Brisse S, Médigue C, Parkhill J, Cruveiller S, Brosch R. 2013. Genomic analysis of smooth tubercle bacilli provides insights into ancestry and pathoadaptation of Mycobacterium tuberculosis. Nat Genet 45:172–179. http://dx.doi.org/10.1038/ng.2517. [PubMed]
57. Boritsch EC, Frigui W, Cascioferro A, Malaga W, Etienne G, Laval F, Pawlik A, Le Chevalier F, Orgeur M, Ma L, Bouchier C, Stinear TP, Supply P, Majlessi L, Daffé M, Guilhot C, Brosch R. 2016. pks5-recombination-mediated surface remodelling in Mycobacterium tuberculosis emergence. Nat Microbiol 1:15019. http://dx.doi.org/10.1038/nmicrobiol.2015.19. [PubMed]
58. Godfroid M, Dagan T, Kupczok A. 2018. Recombination signal in Mycobacterium tuberculosis stems from reference-guided assemblies and alignment artefacts. Genome Biol Evol 10:1920–1926. http://dx.doi.org/10.1093/gbe/evy143. [PubMed]
59. Orgeur M, Brosch R. 2018. Evolution of virulence in the Mycobacterium tuberculosis complex. Curr Opin Microbiol 41:68–75. http://dx.doi.org/10.1016/j.mib.2017.11.021. [PubMed]
60. Ates LS, Brosch R. 2017. Discovery of the type VII ESX-1 secretion needle? Mol Microbiol 103:7–12. http://dx.doi.org/10.1111/mmi.13579. [PubMed]
61. Lewis KN, Liao R, Guinn KM, Hickey MJ, Smith S, Behr MA, Sherman DR. 2003. Deletion of RD1 from Mycobacterium tuberculosis mimics bacille Calmette-Guérin attenuation. J Infect Dis 187:117–123. http://dx.doi.org/10.1086/345862. [PubMed]
62. Hsu T, Hingley-Wilson SM, Chen B, Chen M, Dai AZ, Morin PM, Marks CB, Padiyar J, Goulding C, Gingery M, Eisenberg D, Russell RG, Derrick SC, Collins FM, Morris SL, King CH, Jacobs WR, Jr. 2003. The primary mechanism of attenuation of bacillus Calmette-Guerin is a loss of secreted lytic function required for invasion of lung interstitial tissue. Proc Natl Acad Sci U S A 100:12420–12425. http://dx.doi.org/10.1073/pnas.1635213100. [PubMed]
63. Stanley SA, Raghavan S, Hwang WW, Cox JS. 2003. Acute infection and macrophage subversion by Mycobacterium tuberculosis require a specialized secretion system. Proc Natl Acad Sci U S A 100:13001–13006. http://dx.doi.org/10.1073/pnas.2235593100. [PubMed]
64. Gao LY, Guo S, McLaughlin B, Morisaki H, Engel JN, Brown EJ. 2004. A mycobacterial virulence gene cluster extending RD1 is required for cytolysis, bacterial spreading and ESAT-6 secretion. Mol Microbiol 53:1677–1693. http://dx.doi.org/10.1111/j.1365-2958.2004.04261.x. [PubMed]
65. Pym AS, Brodin P, Brosch R, Huerre M, Cole ST. 2002. Loss of RD1 contributed to the attenuation of the live tuberculosis vaccines Mycobacterium bovis BCG and Mycobacterium microti. Mol Microbiol 46:709–717. http://dx.doi.org/10.1046/j.1365-2958.2002.03237.x. [PubMed]
66. van der Wel N, Hava D, Houben D, Fluitsma D, van Zon M, Pierson J, Brenner M, Peters PJ. 2007. M. tuberculosis and M. leprae translocate from the phagolysosome to the cytosol in myeloid cells. Cell 129:1287–1298. http://dx.doi.org/10.1016/j.cell.2007.05.059. [PubMed]
67. Simeone R, Bobard A, Lippmann J, Bitter W, Majlessi L, Brosch R, Enninga J. 2012. Phagosomal rupture by Mycobacterium tuberculosis results in toxicity and host cell death. PLoS Pathog 8:e1002507. http://dx.doi.org/10.1371/journal.ppat.1002507. [PubMed]
68. Aguilo JI, Alonso H, Uranga S, Marinova D, Arbués A, de Martino A, Anel A, Monzon M, Badiola J, Pardo J, Brosch R, Martin C. 2013. ESX-1-induced apoptosis is involved in cell-to-cell spread of Mycobacterium tuberculosis. Cell Microbiol 15:1994–2005. http://dx.doi.org/10.1111/cmi.12169. [PubMed]
69. Wong KW, Jacobs WR, Jr. 2011. Critical role for NLRP3 in necrotic death triggered by Mycobacterium tuberculosis. Cell Microbiol 13:1371–1384. http://dx.doi.org/10.1111/j.1462-5822.2011.01625.x. [PubMed]
70. Wassermann R, Gulen MF, Sala C, Perin SG, Lou Y, Rybniker J, Schmid-Burgk JL, Schmidt T, Hornung V, Cole ST, Ablasser A. 2015. Mycobacterium tuberculosis differentially activates cGAS- and inflammasome-dependent intracellular immune responses through ESX-1. Cell Host Microbe 17:799–810. http://dx.doi.org/10.1016/j.chom.2015.05.003. [PubMed]
71. Watson RO, Bell SL, MacDuff DA, Kimmey JM, Diner EJ, Olivas J, Vance RE, Stallings CL, Virgin HW, Cox JS. 2015. The cytosolic sensor cGAS detects Mycobacterium tuberculosis DNA to induce type I interferons and activate autophagy. Cell Host Microbe 17:811–819. http://dx.doi.org/10.1016/j.chom.2015.05.004. [PubMed]
72. Collins AC, Cai H, Li T, Franco LH, Li XD, Nair VR, Scharn CR, Stamm CE, Levine B, Chen ZJ, Shiloh MU. 2015. Cyclic GMP-AMP synthase is an innate immune DNA sensor for Mycobacterium tuberculosis. Cell Host Microbe 17:820–828. http://dx.doi.org/10.1016/j.chom.2015.05.005. [PubMed]
73. Majlessi L, Brosch R. 2015. Mycobacterium tuberculosis meets the cytosol: the role of cGAS in anti-mycobacterial immunity. Cell Host Microbe 17:733–735. http://dx.doi.org/10.1016/j.chom.2015.05.017. [PubMed]
74. Kupz A, Zedler U, Stäber M, Perdomo C, Dorhoi A, Brosch R, Kaufmann SH. 2016. ESAT-6-dependent cytosolic pattern recognition drives noncognate tuberculosis control in vivo. J Clin Invest 126:2109–2122. http://dx.doi.org/10.1172/JCI84978. [PubMed]
75. Gröschel MI, Sayes F, Shin SJ, Frigui W, Pawlik A, Orgeur M, Canetti R, Honoré N, Simeone R, van der Werf TS, Bitter W, Cho SN, Majlessi L, Brosch R. 2017. Recombinant BCG expressing ESX-1 of Mycobacterium marinum combines low virulence with cytosolic immune signaling and improved TB protection. Cell Rep 18:2752–2765. http://dx.doi.org/10.1016/j.celrep.2017.02.057. [PubMed]
76. Augenstreich J, Arbues A, Simeone R, Haanappel E, Wegener A, Sayes F, Le Chevalier F, Chalut C, Malaga W, Guilhot C, Brosch R, Astarie-Dequeker C. 2017. ESX-1 and phthiocerol dimycocerosates of Mycobacterium tuberculosis act in concert to cause phagosomal rupture and host cell apoptosis. Cell Microbiol 19:e12726. http://dx.doi.org/10.1111/cmi.12726. [PubMed]
77. Quigley J, Hughitt VK, Velikovsky CA, Mariuzza RA, El-Sayed NM, Briken V. 2017. The cell wall lipid PDIM contributes to phagosomal escape and host cell exit of Mycobacterium tuberculosis. mBio 8:e00148-17. http://dx.doi.org/10.1128/mBio.00148-17. [PubMed]
78. Barczak AK, Avraham R, Singh S, Luo SS, Zhang WR, Bray MA, Hinman AE, Thompson M, Nietupski RM, Golas A, Montgomery P, Fitzgerald M, Smith RS, White DW, Tischler AD, Carpenter AE, Hung DT. 2017. Systematic, multiparametric analysis of Mycobacterium tuberculosis intracellular infection offers insight into coordinated virulence. PLoS Pathog 13:e1006363. http://dx.doi.org/10.1371/journal.ppat.1006363. [PubMed]
79. Skowyra ML, Schlesinger PH, Naismith TV, Hanson PI. 2018. Triggered recruitment of ESCRT machinery promotes endolysosomal repair. Science 360:eaar5-78. http://dx.doi.org/10.1126/science.aar5078. [PubMed]
80. Mehra A, Zahra A, Thompson V, Sirisaengtaksin N, Wells A, Porto M, Köster S, Penberthy K, Kubota Y, Dricot A, Rogan D, Vidal M, Hill DE, Bean AJ, Philips JA. 2013. Mycobacterium tuberculosis type VII secreted effector EsxH targets host ESCRT to impair trafficking. PLoS Pathog 9:e1003734. http://dx.doi.org/10.1371/journal.ppat.1003734. [PubMed]
81. Mittal E, Skowyra ML, Uwase G, Tinaztepe E, Mehra A, Köster S, Hanson PI, Philips JA. 2018. Mycobacterium tuberculosis type VII secretion system effectors differentially impact the ESCRT endomembrane damage response. mBio 9:01765-18. http://dx.doi.org/10.1128/mBio.01765-18. [PubMed]
82. Houben EN, Korotkov KV, Bitter W. 2014. Take five—type VII secretion systems of mycobacteria. Biochim Biophys Acta 1843:1707–1716. http://dx.doi.org/10.1016/j.bbamcr.2013.11.003. [PubMed]
83. Laencina L, Dubois V, Le Moigne V, Viljoen A, Majlessi L, Pritchard J, Bernut A, Piel L, Roux AL, Gaillard JL, Lombard B, Loew D, Rubin EJ, Brosch R, Kremer L, Herrmann JL, Girard-Misguich F. 2018. Identification of genes required for Mycobacterium abscessus growth in vivo with a prominent role of the ESX-4 locus. Proc Natl Acad Sci U S A 115:E1002–E1011. http://dx.doi.org/10.1073/pnas.1713195115. [PubMed]
84. Sayes F, Blanc C, Ates LS, Deboosere N, Orgeur M, Le Chevalier F, Gröschel MI, Frigui W, Song OR, Lo-Man R, Brossier F, Sougakoff W, Bottai D, Brodin P, Charneau P, Brosch R, Majlessi L. 2018. Multiplexed quantitation of intraphagocyte Mycobacterium tuberculosis secreted protein effectors. Cell Rep 23:1072–1084. http://dx.doi.org/10.1016/j.celrep.2018.03.125. [PubMed]
85. Solans L, Gonzalo-Asensio J, Sala C, Benjak A, Uplekar S, Rougemont J, Guilhot C, Malaga W, Martín C, Cole ST. 2014. The PhoP-dependent ncRNA Mcr7 modulates the TAT secretion system in Mycobacterium tuberculosis. PLoS Pathog 10:e1004183. http://dx.doi.org/10.1371/journal.ppat.1004183. [PubMed]
86. Simeone R, Sayes F, Song O, Gröschel MI, Brodin P, Brosch R, Majlessi L. 2015. Cytosolic access of Mycobacterium tuberculosis: critical impact of phagosomal acidification control and demonstration of occurrence in vivo. PLoS Pathog 11:e1004650. http://dx.doi.org/10.1371/journal.ppat.1004650. [PubMed]
87. Pym AS, Brodin P, Majlessi L, Brosch R, Demangel C, Williams A, Griffiths KE, Marchal G, Leclerc C, Cole ST. 2003. Recombinant BCG exporting ESAT-6 confers enhanced protection against tuberculosis. Nat Med 9:533–539. http://dx.doi.org/10.1038/nm859. [PubMed]
88. Bottai D, Frigui W, Clark S, Rayner E, Zelmer A, Andreu N, de Jonge MI, Bancroft GJ, Williams A, Brodin P, Brosch R. 2015. Increased protective efficacy of recombinant BCG strains expressing virulence-neutral proteins of the ESX-1 secretion system. Vaccine 33:2710–2718. http://dx.doi.org/10.1016/j.vaccine.2015.03.083. [PubMed]
89. Gengenbacher M, Nieuwenhuizen N, Vogelzang A, Liu H, Kaiser P, Schuerer S, Lazar D, Wagner I, Mollenkopf HJ, Kaufmann SH. 2016. Deletion of nuoG from the vaccine candidate Mycobacterium bovis BCG Δ ureC:: hly improves protection against tuberculosis. mBio 7:e00679-16. http://dx.doi.org/10.1128/mBio.00679-16. [PubMed]
90. Ates LS, Sayes F, Frigui W, Ummels R, Damen MPM, Bottai D, Behr MA, van Heijst JWJ, Bitter W, Majlessi L, Brosch R. 2018. RD5-mediated lack of PE_PGRS and PPE-MPTR export in BCG vaccine strains results in strong reduction of antigenic repertoire but little impact on protection. PLoS Pathog 14:e1007139. http://dx.doi.org/10.1371/journal.ppat.1007139. [PubMed]
91. Aguilo N, Gonzalo-Asensio J, Alvarez-Arguedas S, Marinova D, Gomez AB, Uranga S, Spallek R, Singh M, Audran R, Spertini F, Martin C. 2017. Reactogenicity to major tuberculosis antigens absent in BCG is linked to improved protection against Mycobacterium tuberculosis. Nat Commun 8:16085. http://dx.doi.org/10.1038/ncomms16085. [PubMed]
92. Sayes F, Pawlik A, Frigui W, Gröschel MI, Crommelynck S, Fayolle C, Cia F, Bancroft GJ, Bottai D, Leclerc C, Brosch R, Majlessi L. 2016. CD4+ T cells recognizing PE/PPE antigens directly or via cross reactivity are protective against pulmonary Mycobacterium tuberculosis infection. PLoS Pathog 12:e1005770. http://dx.doi.org/10.1371/journal.ppat.1005770. [PubMed]
93. Marinova D, Gonzalo-Asensio J, Aguilo N, Martin C. 2017. MTBVAC from discovery to clinical trials in tuberculosis-endemic countries. Expert Rev Vaccines 16:565–576. http://dx.doi.org/10.1080/14760584.2017.1324303. [PubMed]

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The causative agent of human tuberculosis, , has a complex lipid-rich diderm envelope, which acts as a major barrier protecting the bacterium against the hostile environment inside the host cells. For the transfer of diverse molecules across this complex cell envelope, has a series of general and specialized protein secretion systems, characterized by the SecA general secretion pathway, the twin-arginine translocation pathway, and five specific ESX type VII secretion systems. In this review, we focus on the latter systems, known as ESX-1 to ESX-5, which were first discovered almost 20 years ago during the analysis of the genome sequence of H37Rv. Since then, these systems have been the subject of highly dynamic research due to their involvement in several key biological processes and host-pathogen interactions of the tubercle bacilli.

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Image of FIGURE 1

Genetic organization of the ESX loci. Shown is a schematic representation of the approximative genomic sites of the ESX-1 to ESX-5 clusters in the H37Rv genome. Gene nomenclature and gene color scheme were adapted from reference 16 .

Source: microbiolspec July 2019 vol. 7 no. 4 doi:10.1128/microbiolspec.PSIB-0029-2019
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Image of FIGURE 2

Representation of top and side views of the ESX/T7S system based on recent structural data generated by cryo-electron microscopy and single-particle analysis on an ESX-5 system from , in comparison to selected examples of secretion systems from Gram-negative bacteria. The positions of the inner membrane (IM), outer membrane (OM), and mycomembrane (MM) are indicated. Adapted from reference 10 , with permission.

Source: microbiolspec July 2019 vol. 7 no. 4 doi:10.1128/microbiolspec.PSIB-0029-2019
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Image of FIGURE 3

Interplay of ESX-1 and ESX-3 in host-pathogen interactions. ESX-1 is essential for the bacterial phagosome-to-cytosol transition by involving a cGAS/STING/TBK1/IRF-3/type I interferon signalling axis and AIM2 and NLRP3 inflammasome activities. In an ESX-1-dependent manner, the ESCRT machinery is recruited to phagosomes, while ESX-3 effectors (EsxG-EsxH) antagonize the host damage response by blocking the recruitment of HRS, ESCRT-III, and GAL3. The scheme is adapted from reference 11 , with some additions from reference 81 , with permission.

Source: microbiolspec July 2019 vol. 7 no. 4 doi:10.1128/microbiolspec.PSIB-0029-2019
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