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Infect and Inject: How Exploits Its Major Virulence-Associated Type VII Secretion System, ESX-1

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  • Authors: Sangeeta Tiwari1, Rosalyn Casey2, Celia W. Goulding3, Suzie Hingley-Wilson4, William R. Jacobs, Jr. Jr.5
  • Editors: Pascale Cossart6, Craig R. Roy7, Philippe Sansonetti8
    Affiliations: 1: Department of Microbiology and Immunology, Albert Einstein College of Medicine, Bronx, NY 10461; 2: Department of Microbial Sciences, School of Biosciences and Medicine, University of Surrey, Guilford, Surrey, GU27XH, United Kingdom; 3: Department of Molecular Biology & Biochemistry and Department of Pharmaceutical Sciences, University of California Irvine, Irvine, CA 92697; 4: Department of Microbial Sciences, School of Biosciences and Medicine, University of Surrey, Guilford, Surrey, GU27XH, United Kingdom; 5: Department of Microbiology and Immunology, Albert Einstein College of Medicine, Bronx, NY 10461; 6: Institut Pasteur, Paris, France; 7: Yale University School of Medicine, New Haven, Connecticut; 8: Institut Pasteur, Paris, France
  • Source: microbiolspec June 2019 vol. 7 no. 3 doi:10.1128/microbiolspec.BAI-0024-2019
  • Received 09 April 2019 Accepted 12 April 2019 Published 07 June 2019
  • William R. Jacobs, Jr., [email protected]; Sangeeta Tiwari, [email protected]
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  • Abstract:

    is an ancient master of the art of causing human disease. One important weapon within its fully loaded arsenal is the type VII secretion system. has five of them: ESAT-6 secretion systems (ESX) 1 to 5. ESX-1 has long been recognized as a major cause of attenuation of the FDA-licensed vaccine BCG, but its importance in disease progression and transmission has recently been elucidated in more detail. This review summarizes the recent advances in (i) the understanding of the ESX-1 structure and components, (ii) our knowledge of ESX-1’s role in hijacking macrophage function to set a path for infection and dissemination, and (iii) the development of interventions that utilize ESX-1 for diagnosis, drug interventions, host-directed therapies, and vaccines.

  • Citation: Tiwari S, Casey R, Goulding C, Hingley-Wilson S, Jacobs, Jr. W. 2019. Infect and Inject: How Exploits Its Major Virulence-Associated Type VII Secretion System, ESX-1. Microbiol Spectrum 7(3):BAI-0024-2019. doi:10.1128/microbiolspec.BAI-0024-2019.


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is an ancient master of the art of causing human disease. One important weapon within its fully loaded arsenal is the type VII secretion system. has five of them: ESAT-6 secretion systems (ESX) 1 to 5. ESX-1 has long been recognized as a major cause of attenuation of the FDA-licensed vaccine BCG, but its importance in disease progression and transmission has recently been elucidated in more detail. This review summarizes the recent advances in (i) the understanding of the ESX-1 structure and components, (ii) our knowledge of ESX-1’s role in hijacking macrophage function to set a path for infection and dissemination, and (iii) the development of interventions that utilize ESX-1 for diagnosis, drug interventions, host-directed therapies, and vaccines.

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Image of FIGURE 1

Schematic of the ESX-1 secretion system. Gene map of the locus and the operon in H37Rv. The locus includes genes encoding the secreted effector proteins EsxA and EsxB alongside genes encoding ESX-conserved proteins and genes encoding ESX secretion-associated proteins ( 108 ). The operon is at a locus distinct from the locus but shares sequence homology with , , and of (dashed lines). The spontaneous deletion (Rv3871 to Rv3878) from found in the vaccine strains of BCG is known as region of difference 1 (RD1) and is indicated by the gray box. Model of the ESX-1 secretion system in the mycobacterial cell envelope. In common with all ESX systems, the core structure of the ESX-1 secretion apparatus starts with the inner membrane-spanning conserved components EccB, EccC, EccD, and EccE ( 109 ). EccC is an ATP-driven translocase consisting of two subunits (a and b) that are assembled following EccB binding of target substrate, in this case, the heterodimer EsxAB, where EccCb interacts with the carboxyl-terminal signal sequence of EsxB (labeled “C”) ( 21 , 110 ). EsxAB secretion is codependent on the secretion of EspC/EspA, which is also dependent on interaction with the cytosolic ATPase EccA ( 20 , 111 ). EspC polymerizes during secretion, indicating a role for EccA and EspA as cytosolic chaperones ( 18 ), and forms a filamentous structure thought to provide a channel for secretion of ESX-1 substrates ( 18 ). Other important ESX-1 substrates include the PE and PPE families of proteins, which form heterodimers and are recruited by the putative cytosolic chaperone EspG to initiate interaction with the core complex of proteins within the inner membrane ( 112 114 ). EspB is also secreted by ESX-1 and forms a PE-PPE-like fold, containing a C-terminal domain that is processed by the MycP protease during secretion ( 26 , 115 ). EspD to -F and EspH proteins are cytosolic and were recently shown to be stabilized by the cytosolic chaperone EspL ( 24 26 ).

Source: microbiolspec June 2019 vol. 7 no. 3 doi:10.1128/microbiolspec.BAI-0024-2019
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Image of FIGURE 2

ESX-1-related disease progression within the lung. Steps involved in progression of disease are represented with the numbers 1 to 9. (1) Infection of alveolar macrophages with (wild type) or ESX-1 mutant. (2) Lysis of the phagosomal and cellular macrophage membranes is carried out by EsxA from wild-type (2a), while the ESX-1 mutant remains trapped in the alveolar macrophages in the alveolar space (2b). (3) Infection of type II pneumocytes in the alveolar epithelium (AE) by , with resulting ESAT-6-mediated lysis, allowing passage into the interstitial tissue or (3a) translocation of infected alveolar macrophage to lung interstitial tissue. (4) Translocated bacteria are ingested by and replicate within macrophages, which produce cytokines such as fractalkine. (5) Release of bacilli by necrosis of infection-dependent macrophages. (6) Recruitment of neutrophils and naive macrophages by fractalkine and infection of new macrophages and other cells by phagocytosis. (7) Intracellular replication of bacilli in recruited infected macrophages. (8) Continuation of the cycle, leading to egress of from the host cells into deeper interstitial tissue and dissemination within the lungs. (9) Establishment of granulomas and necrosis. (Insets) (a) Electron micrograph of EsxAB. (b) Electron micrograph of the ESX-1 mutant (blue arrow) trapped within the phagosome of an alveolar macrophage in alveolar space in a murine model. (c) Electron micrograph showing wild-type (red arrow) following egress to the cytoplasm and interstitial spaces in the murine lung.

Source: microbiolspec June 2019 vol. 7 no. 3 doi:10.1128/microbiolspec.BAI-0024-2019
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Image of FIGURE 3

TB vaccines in the pipeline, undergoing phase 1 to 3 clinical trials. Current vaccine candidates in the pipeline include protein/adjuvant-based, attenuated/killed or cell extract-based, and viral vector-based vaccines.

Source: microbiolspec June 2019 vol. 7 no. 3 doi:10.1128/microbiolspec.BAI-0024-2019
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