Chapter 29 : The Role of ESX-1 in Pathogenesis

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The identification of ESAT-6 secretion system-1 (ESX-1) as a virulence determinant of is a major discovery in the history of tuberculosis research. ESX-1 is encoded by a genetic locus known as RD1, which stands for “region of difference” and is one of the deleted regions in the vaccine strain bacille Calmette-Guérin (BCG) for humans ( ). The first evidence emerges from the finding that the absence of RD1 is responsible for the attenuation of BCG’s virulence ( ). Introduction of RD1 into BCG is sufficient to induce BCG growth in lung and spleen, granuloma formation in lung, splenomegaly, and inflammation and abscesses in liver and kidney in mice ( ). Conversely, deletion of RD1 in the virulent H37Rv strain inactivates the ability of H37Rv to enable rapid bacterial replication in lung and spleen, to cause lung histopathology and death in mice ( ). Lung sections from infected mice show evidence of macrophage lysis, which is a RD1-dependent process ( ). Consistent with this observation, Lewis et al. describe the requirement of RD1 for H37Rv to grow within and kill human macrophages ( ).

Citation: Wong K. 2017. The Role of ESX-1 in Pathogenesis, p 627-634. In Jacobs, Jr. W, McShane H, Mizrahi V, Orme I (ed), Tuberculosis and the Tubercle Bacillus, Second Edition. ASM Press, Washington, DC. doi: 10.1128/microbiolspec.TBTB2-0001-2015
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1. Behr MA,, Wilson MA,, Gill WP,, Salamon H,, Schoolnik GK,, Rane S,, Small PM . 1999. Comparative genomics of BCG vaccines by whole-genome DNA microarray. Science 284 : 1520 1523. [CrossRef] [PubMed]
2. 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 USA 100 : 12420 12425. [CrossRef]
3. 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. [CrossRef]
4. 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. [CrossRef]
5. Russell DG,, Cardona PJ,, Kim MJ,, Allain S,, Altare F . 2009. Foamy macrophages and the progression of the human tuberculosis granuloma. Nat Immunol 10 : 943 948. [CrossRef] [PubMed]
6. 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. [CrossRef] [PubMed]
7. Armstrong JA,, Hart PD . 1971. Response of cultured macrophages to Mycobacterium tuberculosis, with observations on fusion of lysosomes with phagosomes. J Exp Med 134 : 713 740. [CrossRef] [PubMed]
8. 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. [CrossRef]
9. Houben D,, Demangel C,, van Ingen J,, Perez J,, Baldeón L,, Abdallah AM,, Caleechurn L,, Bottai D,, van Zon M,, de Punder K,, van der Laan T,, Kant A,, Bossers-de Vries R,, Willemsen P,, Bitter W,, van Soolingen D,, Brosch R,, van der Wel N,, Peters PJ . 2012. ESX-1-mediated translocation to the cytosol controls virulence of mycobacteria. Cell Microbiol 14 : 1287 1298. [CrossRef]
10. McDonough KA,, Kress Y,, Bloom BR . 1993. Pathogenesis of tuberculosis: interaction of Mycobacterium tuberculosis with macrophages. Infect Immun 61 : 2763 2773.[PubMed]
11. Huynh KK,, Eskelinen EL,, Scott CC,, Malevanets A,, Saftig P,, Grinstein S . 2007. LAMP proteins are required for fusion of lysosomes with phagosomes. EMBO J 26 : 313 324. [CrossRef]
12. Leake ES,, Myrvik QN,, Wright MJ . 1984. Phagosomal membranes of Mycobacterium bovis BCG-immune alveolar macrophages are resistant to disruption by Mycobacterium tuberculosis H37Rv. Infect Immun 45 : 443 446.[PubMed]
13. Myrvik QN,, Leake ES,, Wright MJ . 1984. Disruption of phagosomal membranes of normal alveolar macrophages by the H37Rv strain of Mycobacterium tuberculosis. A correlate of virulence. Am Rev Respir Dis 129 : 322 328.[PubMed]
14. Paz I,, Sachse M,, Dupont N,, Mounier J,, Cederfur C,, Enninga J,, Leffler H,, Poirier F,, Prevost MC,, Lafont F,, Sansonetti P . 2010. Galectin-3, a marker for vacuole lysis by invasive pathogens. Cell Microbiol 12 : 530 544. [CrossRef] [PubMed]
15. Wong KW,, Jacobs WR Jr . 2011. Critical role for NLRP3 in necrotic death triggered by Mycobacterium tuberculosis . Cell Microbiol 13 : 1371 1384. [CrossRef]
16. 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.[CrossRef]
17. 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.[CrossRef]
18. Vance RE,, Isberg RR,, Portnoy DA . 2009. Patterns of pathogenesis: discrimination of pathogenic and nonpathogenic microbes by the innate immune system. Cell Host Microbe 6 : 10 21. [CrossRef]
19. Mishra BB,, Moura-Alves P,, Sonawane A,, Hacohen N,, Griffiths G,, Moita LF,, Anes E . 2010. Mycobacterium tuberculosis protein ESAT-6 is a potent activator of the NLRP3/ASC inflammasome. Cell Microbiol 12 : 1046 1063. [CrossRef]
20. Schneider BE,, Korbel D,, Hagens K,, Koch M,, Raupach B,, Enders J,, Kaufmann SH,, Mittrücker HW,, Schaible UE . 2010. A role for IL-18 in protective immunity against Mycobacterium tuberculosis . Eur J Immunol 40 : 396 405. [CrossRef]
21. Mayer-Barber KD,, Barber DL,, Shenderov K,, White SD,, Wilson MS,, Cheever A,, Kugler D,, Hieny S,, Caspar P,, Núñez G,, Schlueter D,, Flavell RA,, Sutterwala FS,, Sher A . 2010. Caspase-1 independent IL-1beta production is critical for host resistance to Mycobacterium tuberculosis and does not require TLR signaling in vivo. J Immunol 184 : 3326 3330. [CrossRef]
22. Orme IM . 2014. A new unifying theory of the pathogenesis of tuberculosis. Tuberculosis (Edinb) 94 : 8 14. [CrossRef]
23. Compan V,, Baroja-Mazo A,, López-Castejón G,, Gomez AI,, Martínez CM,, Angosto D,, Montero MT,, Herranz AS,, Bazán E,, Reimers D,, Mulero V,, Pelegrín P . 2012. Cell volume regulation modulates NLRP3 inflammasome activation. Immunity 37 : 487 500. [CrossRef]
24. Ip WK,, Medzhitov R . 2015. Macrophages monitor tissue osmolarity and induce inflammatory response through NLRP3 and NLRC4 inflammasome activation. Nat Commun 6 : 6931. [CrossRef]
25. King CH,, Mundayoor S,, Crawford JT,, Shinnick TM . 1993. Expression of contact-dependent cytolytic activity by Mycobacterium tuberculosis and isolation of the genomic locus that encodes the activity. Infect Immun 61 : 2708 2712.[PubMed]
26. Stanley SA,, Johndrow JE,, Manzanillo P,, Cox JS . 2007. The Type I IFN response to infection with Mycobacterium tuberculosis requires ESX-1-mediated secretion and contributes to pathogenesis. J Immunol 178 : 3143 3152. [CrossRef]
27. Manzanillo PS,, Shiloh MU,, Portnoy DA,, Cox JS . 2012. Mycobacterium tuberculosis activates the DNA-dependent cytosolic surveillance pathway within macrophages. Cell Host Microbe 11 : 469 480. [CrossRef]
28. 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. [CrossRef]
29. 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. [CrossRef]
30. 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. [CrossRef]
31. Antonelli LR,, Gigliotti Rothfuchs A,, Gonçalves R,, Roffê E,, Cheever AW,, Bafica A,, Salazar AM,, Feng CG,, Sher A . 2010. Intranasal poly-IC treatment exacerbates tuberculosis in mice through the pulmonary recruitment of a pathogen-permissive monocyte/macrophage population. J Clin Invest 120 : 1674 1682. [CrossRef]
32. Mayer-Barber KD,, Andrade BB,, Oland SD,, Amaral EP,, Barber DL,, Gonzales J,, Derrick SC,, Shi R,, Kumar NP,, Wei W,, Yuan X,, Zhang G,, Cai Y,, Babu S,, Catalfamo M,, Salazar AM,, Via LE,, Barry CE III,, Sher A . 2014. Host-directed therapy of tuberculosis based on interleukin-1 and type I interferon crosstalk. Nature 511 : 99 103. [CrossRef]
33. Shah S,, Bohsali A,, Ahlbrand SE,, Srinivasan L,, Rathinam VA,, Vogel SN,, Fitzgerald KA,, Sutterwala FS,, Briken V . 2013. Cutting edge: mycobacterium tuberculosis but not nonvirulent mycobacteria inhibits IFN-β and AIM2 inflammasome-dependent IL-1β production via its ESX-1 secretion system. J Immunol 191 : 3514 3518. [CrossRef] [PubMed]
34. Berry MP,, Graham CM,, McNab FW,, Xu Z,, Bloch SA,, Oni T,, Wilkinson KA,, Banchereau R,, Skinner J,, Wilkinson RJ,, Quinn C,, Blankenship D,, Dhawan R,, Cush JJ,, Mejias A,, Ramilo O,, Kon OM,, Pascual V,, Banchereau J,, Chaussabel D,, O’Garra A . 2010. An interferon-inducible neutrophil-driven blood transcriptional signature in human tuberculosis. Nature 466 : 973 977. [CrossRef]
35. Inohara N,, Nuñez G . 2003. NODs: intracellular proteins involved in inflammation and apoptosis. Nat Rev Immunol 3 : 371 382. [CrossRef]
36. Pandey AK,, Yang Y,, Jiang Z,, Fortune SM,, Coulombe F,, Behr MA,, Fitzgerald KA,, Sassetti CM,, Kelliher MA . 2009. NOD2, RIP2 and IRF5 play a critical role in the type I interferon response to Mycobacterium tuberculosis . PLoS Pathog 5 : e1000500.[CrossRef]
37. 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. [CrossRef]
38. Yao Q . 2013. Nucleotide-binding oligomerization domain containing 2: structure, function, and diseases. Semin Arthritis Rheum 43 : 125 130. [CrossRef]
39. Gutierrez MG,, Master SS,, Singh SB,, Taylor GA,, Colombo MI,, Deretic V . 2004. Autophagy is a defense mechanism inhibiting BCG and Mycobacterium tuberculosis survival in infected macrophages. Cell 119 : 753 766. [CrossRef]
40. Manzanillo PS,, Ayres JS,, Watson RO,, Collins AC,, Souza G,, Rae CS,, Schneider DS,, Nakamura K,, Shiloh MU,, Cox JS . 2013. The ubiquitin ligase parkin mediates resistance to intracellular pathogens. Nature 501 : 512 516. [CrossRef]
41. Geisler S,, Holmström KM,, Skujat D,, Fiesel FC,, Rothfuss OC,, Kahle PJ,, Springer W . 2010. PINK1/Parkin-mediated mitophagy is dependent on VDAC1 and p62/SQSTM1. Nat Cell Biol 12 : 119 131. [CrossRef]
42. Watson RO,, Manzanillo PS,, Cox JS . 2012. Extracellular M. tuberculosis DNA targets bacteria for autophagy by activating the host DNA-sensing pathway. Cell 150 : 803 815. [CrossRef]
43. Romagnoli A,, Etna MP,, Giacomini E,, Pardini M,, Remoli ME,, Corazzari M,, Falasca L,, Goletti D,, Gafa V,, Simeone R,, Delogu G,, Piacentini M,, Brosch R,, Fimia GM,, Coccia EM . 2012. ESX-1 dependent impairment of autophagic flux by Mycobacterium tuberculosis in human dendritic cells. Autophagy 8 : 1357 1370. [CrossRef]
44. Brodin P,, Poquet Y,, Levillain F,, Peguillet I,, Larrouy-Maumus G,, Gilleron M,, Ewann F,, Christophe T,, Fenistein D,, Jang J,, Jang MS,, Park SJ,, Rauzier J,, Carralot JP,, Shrimpton R,, Genovesio A,, Gonzalo-Asensio JA,, Puzo G,, Martin C,, Brosch R,, Stewart GR,, Gicquel B,, Neyrolles O . 2010. High content phenotypic cell-based visual screen identifies Mycobacterium tuberculosis acyltrehalose-containing glycolipids involved in phagosome remodeling. PLoS Pathog 6 : e1001100.[CrossRef]
45. MacGurn JA,, Cox JS . 2007. A genetic screen for Mycobacterium tuberculosis mutants defective for phagosome maturation arrest identifies components of the ESX-1 secretion system. Infect Immun 75 : 2668 2678. [CrossRef]
46. 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.[CrossRef]
47. Wong D,, Bach H,, Sun J,, Hmama Z,, Av-Gay Y . 2011. Mycobacterium tuberculosis protein tyrosine phosphatase (PtpA) excludes host vacuolar-H+-ATPase to inhibit phagosome acidification. Proc Natl Acad Sci USA 108 : 19371 19376. [CrossRef]
48. Vergne I,, Chua J,, Lee HH,, Lucas M,, Belisle J,, Deretic V . 2005. Mechanism of phagolysosome biogenesis block by viable Mycobacterium tuberculosis . Proc Natl Acad Sci USA 102 : 4033 4038. [CrossRef]
49. Kirby JE,, Vogel JP,, Andrews HL,, Isberg RR . 1998. Evidence for pore-forming ability by Legionella pneumophila . Mol Microbiol 27 : 323 336. [CrossRef]
50. Lansbury PT Jr . 1999. Evolution of amyloid: what normal protein folding may tell us about fibrillogenesis and disease. Proc Natl Acad Sci USA 96 : 3342 3344. [CrossRef]
51. Demuro A,, Mina E,, Kayed R,, Milton SC,, Parker I,, Glabe CG . 2005. Calcium dysregulation and membrane disruption as a ubiquitous neurotoxic mechanism of soluble amyloid oligomers. J Biol Chem 280 : 17294 17300. [CrossRef]
52. Wang L,, Maji SK,, Sawaya MR,, Eisenberg D,, Riek R . 2008. Bacterial inclusion bodies contain amyloid-like structure. PLoS Biol 6 : e195.[CrossRef]
53. Reardon S . 2015. Antibody drugs for Alzheimer’s show glimmers of promise. Nature 523 : 509 510. [CrossRef]
54. Frigui W,, Bottai D,, Majlessi L,, Monot M,, Josselin E,, Brodin P,, Garnier T,, Gicquel B,, Martin C,, Leclerc C,, Cole ST,, Brosch R . 2008. Control of M. tuberculosis ESAT-6 secretion and specific T cell recognition by PhoP. PLoS Pathog 4 : e33. [CrossRef]
55. Lee JS,, Krause R,, Schreiber J,, Mollenkopf HJ,, Kowall J,, Stein R,, Jeon BY,, Kwak JY,, Song MK,, Patron JP,, Jorg S,, Roh K,, Cho SN,, Kaufmann SH . 2008. Mutation in the transcriptional regulator PhoP contributes to avirulence of Mycobacterium tuberculosis H37Ra strain. Cell Host Microbe 3 : 97 103. [CrossRef]
56. 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 USA 102 : 10676 10681. [CrossRef]
57. Cao G,, Howard ST,, Zhang P,, Wang X,, Chen XL,, Samten B,, Pang X . 2015. EspR, a regulator of the ESX-1 secretion system in Mycobacterium tuberculosis, is directly regulated by the two-component systems MprAB and PhoPR. Microbiology 161 : 477 489. [CrossRef]
58. Raghavan S,, Manzanillo P,, Chan K,, Dovey C,, Cox JS . 2008. Secreted transcription factor controls Mycobacterium tuberculosis virulence. Nature 454 : 717 721. [CrossRef]
59. Tan S,, Sukumar N,, Abramovitch RB,, Parish T,, Russell DG . 2013. Mycobacterium tuberculosis responds to chloride and pH as synergistic cues to the immune status of its host cell. PLoS Pathog 9 : e1003282. [CrossRef]
60. Via LE,, Fratti RA,, McFalone M,, Pagan-Ramos E,, Deretic D,, Deretic V . 1998. Effects of cytokines on mycobacterial phagosome maturation. J Cell Sci 111 : 897 905.[PubMed]
61. Denis M . 1991. Interferon-gamma-treated murine macrophages inhibit growth of tubercle bacilli via the generation of reactive nitrogen intermediates. Cell Immunol 132 : 150 157. [CrossRef]
62. Herbst S,, Schaible UE,, Schneider BE . 2011. Interferon gamma activated macrophages kill mycobacteria by nitric oxide induced apoptosis. PLoS One 6 : e19105.[CrossRef]
63. Warwick-Davies J,, Dhillon J,, O’Brien L,, Andrew PW,, Lowrie DB . 1994. Apparent killing of Mycobacterium tuberculosis by cytokine-activated human monocytes can be an artefact of a cytotoxic effect on the monocytes. Clin Exp Immunol 96 : 214 217. [CrossRef]
64. Wong KW,, Jacobs WR Jr . 2013. Mycobacterium tuberculosis exploits human interferon γ to stimulate macrophage extracellular trap formation and necrosis. J Infect Dis 208 : 109 119. [CrossRef]
65. Zhang M,, Chen JM,, Sala C,, Rybniker J,, Dhar N,, Cole ST . 2014. EspI regulates the ESX-1 secretion system in response to ATP levels in Mycobacterium tuberculosis . Mol Microbiol 93 : 1057 1065. [CrossRef] [PubMed]
66. Chen JM,, Zhang M,, Rybniker J,, Boy-Röttger S,, Dhar N,, Pojer F,, Cole ST . 2013. Mycobacterium tuberculosis EspB binds phospholipids and mediates EsxA-independent virulence. Mol Microbiol 89 : 1154 1166. [CrossRef]
67. Martin CJ,, Booty MG,, Rosebrock TR,, Nunes-Alves C,, Desjardins DM,, Keren I,, Fortune SM,, Remold HG,, Behar SM . 2012. Efferocytosis is an innate antibacterial mechanism. Cell Host Microbe 12 : 289 300. [CrossRef]
68. Huang D,, Bao L . 2016. Mycobacterium tuberculosis EspB protein suppresses interferon-γ-induced autophagy in murine macrophages. J Microbiol Immunol Infect 49 : 859 865. 10.1016/j.jmii.2014.11.008. [PubMed]
69. Bruntz RC,, Lindsley CW,, Brown HA . 2014. Phospholipase D signaling pathways and phosphatidic acid as therapeutic targets in cancer. Pharmacol Rev 66 : 1033 1079. [CrossRef] [PubMed]
70. Korotkova N,, Piton J,, Wagner JM,, Boy-Röttger S,, Japaridze A,, Evans TJ,, Cole ST,, Pojer F,, Korotkov KV . 2015. Structure of EspB, a secreted substrate of the ESX-1 secretion system of Mycobacterium tuberculosis . J Struct Biol 191 : 236 244. [CrossRef]
71. Solomonson M,, Setiaputra D,, Makepeace KA,, Lameignere E,, Petrotchenko EV,, Conrady DG,, Bergeron JR,, Vuckovic M,, DiMaio F,, Borchers CH,, Yip CK,, Strynadka NC . 2015. Structure of EspB from the ESX-1 type VII secretion system and insights into its export mechanism. Structure 23 : 571 583. [CrossRef] [PubMed]
72. Rybniker J,, Chen JM,, Sala C,, Hartkoorn RC,, Vocat A,, Benjak A,, Boy-Röttger S,, Zhang M,, Székely R,, Greff Z,, Orfi L,, Szabadkai I,, Pató J,, Kéri G,, Cole ST . 2014. Anticytolytic screen identifies inhibitors of mycobacterial virulence protein secretion. Cell Host Microbe 16 : 538 548. [CrossRef]
73. Johnson BK,, Colvin CJ,, Needle DB,, Mba Medie F,, Champion PA,, Abramovitch RB . 2015. The carbonic anhydrase inhibitor ethoxzolamide inhibits the Mycobacterium tuberculosis PhoPR regulon and Esx-1 secretion and attenuates virulence. Antimicrob Agents Chemother 59 : 4436 4445. [CrossRef]

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