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Mechanism and Function of Type IV Secretion During Infection of the Human Host

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  • Authors: Christian Gonzalez-Rivera1, Minny Bhatty2, Peter J. Christie3
  • Editor: Indira T. Kudva4
    Affiliations: 1: Department of Microbiology and Molecular Genetics, University of Texas Medical School at Houston, Houston, TX 77030; 2: Department of Microbiology and Molecular Genetics, University of Texas Medical School at Houston, Houston, TX 77030; 3: Department of Microbiology and Molecular Genetics, University of Texas Medical School at Houston, Houston, TX 77030; 4: National Animal Disease Center, Agricultural Research Service, U.S. Department of Agriculture, Ames, IA
  • Source: microbiolspec May 2016 vol. 4 no. 3 doi:10.1128/microbiolspec.VMBF-0024-2015
  • Received 19 July 2015 Accepted 22 October 2015 Published 06 May 2016
  • Peter J. Christie, [email protected]
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  • Abstract:

    Bacterial pathogens employ type IV secretion systems (T4SSs) for various purposes to aid in survival and proliferation in eukaryotic hosts. One large T4SS subfamily, the conjugation systems, confers a selective advantage to the invading pathogen in clinical settings through dissemination of antibiotic resistance genes and virulence traits. Besides their intrinsic importance as principle contributors to the emergence of multiply drug-resistant “superbugs,” detailed studies of these highly tractable systems have generated important new insights into the mode of action and architectures of paradigmatic T4SSs as a foundation for future efforts aimed at suppressing T4SS machine function. Over the past decade, extensive work on the second large T4SS subfamily, the effector translocators, has identified a myriad of mechanisms employed by pathogens to subvert, subdue, or bypass cellular processes and signaling pathways of the host cell. An overarching theme in the evolution of many effectors is that of molecular mimicry. These effectors carry domains similar to those of eukaryotic proteins and exert their effects through stealthy interdigitation of cellular pathways, often with the outcome not of inducing irreversible cell damage but rather of reversibly modulating cellular functions. This article summarizes the major developments for the actively studied pathogens with an emphasis on the structural and functional diversity of the T4SSs and the emerging common themes surrounding effector function in the human host.

  • Citation: Gonzalez-Rivera C, Bhatty M, Christie P. 2016. Mechanism and Function of Type IV Secretion During Infection of the Human Host. Microbiol Spectrum 4(3):VMBF-0024-2015. doi:10.1128/microbiolspec.VMBF-0024-2015.


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Bacterial pathogens employ type IV secretion systems (T4SSs) for various purposes to aid in survival and proliferation in eukaryotic hosts. One large T4SS subfamily, the conjugation systems, confers a selective advantage to the invading pathogen in clinical settings through dissemination of antibiotic resistance genes and virulence traits. Besides their intrinsic importance as principle contributors to the emergence of multiply drug-resistant “superbugs,” detailed studies of these highly tractable systems have generated important new insights into the mode of action and architectures of paradigmatic T4SSs as a foundation for future efforts aimed at suppressing T4SS machine function. Over the past decade, extensive work on the second large T4SS subfamily, the effector translocators, has identified a myriad of mechanisms employed by pathogens to subvert, subdue, or bypass cellular processes and signaling pathways of the host cell. An overarching theme in the evolution of many effectors is that of molecular mimicry. These effectors carry domains similar to those of eukaryotic proteins and exert their effects through stealthy interdigitation of cellular pathways, often with the outcome not of inducing irreversible cell damage but rather of reversibly modulating cellular functions. This article summarizes the major developments for the actively studied pathogens with an emphasis on the structural and functional diversity of the T4SSs and the emerging common themes surrounding effector function in the human host.

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Bacterial pathogens employing type IV secretion systems (T4SSs) for establishment within the human host, acquisition of DNA encoding virulence traits, or out-competition of other bacteria for niche occupation. Extracellular pathogens deliver substrates to human or plant cells by contact-dependent or -independent mechanisms. These pathogens deliver diverse substrates including oncogenic T-DNA, monomeric CagA, and multimeric pertussis toxin. Facultative intracellular pathogens enter the host cell from an environmental sample, whereas obligate intracellular pathogens enter directly from another host cell. The intracellular pathogens employ T4SSs to deliver a myriad of effectors whose collective function is to subvert host cellular processes principally for establishment of replicative niches. Shown are T4SSs on the bacterial cell envelope (red trapezoids), effectors (proteins: multicolor circles; tDNA: red wavy line), and various target organelles/sites of effector action within the host cell. T4SSs also mediate interbacterial transfer by contact-dependent mechanisms for conjugative DNA transfer or to kill neighboring bacteria (red X), or by contact-independent mechanisms to exchange DNA with the environment.

Source: microbiolspec May 2016 vol. 4 no. 3 doi:10.1128/microbiolspec.VMBF-0024-2015
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Schematic of the VirB/VirB type IV secretion system (T4SS). (Lower) genes are expressed from the same promoter, and from a separate promoter (indicated by two slashes). (Upper) The VirB and VirD4 subunits assemble as the translocation channel, which presents as two subcomplexes termed the outer membrane complex (OMC), composed of VirB7, VirB9, VirB10, and VirB2, and the inner membrane complex (IMC), composed of VirB3, VirB4, VirB6, VirB8, VirB11, and VirD4. VirB2, VirB5, and a proteolytic fragment of VirB1 (B1*) also assemble as the conjugative pilus without a requirement for VirD4. The physical and functional relationships between the translocation channel and the conjugative pilus are not yet known. OM, outer membrane; CW, cell wall; CM, cytoplasmic membrane. See references 24 , 25 , and 237 for recent structures of related T4SSs. Adapted from 2013. The expanding bacterial type IV secretion lexicon. Res Microbiol 620–629. Copyright 2013, Institut Pasteur, published by Elsevier Masson SAS. All rights reserved.

Source: microbiolspec May 2016 vol. 4 no. 3 doi:10.1128/microbiolspec.VMBF-0024-2015
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Type IV secretion system effectors and cellular consequences of translocation by extracellular pathogens. and deliver substrates through direct cell–cell contact, and does so by a contact-independent mechanism. Pathogens target the host cell types listed. Translocated effectors interact (red arrows; dash denotes indirect interaction) with host cell proteins (light green boxes) to modulate various cellular processes and signaling pathways. Cellular consequences of the effector–host protein interactions (black arrows) are listed (aqua boxes).

Source: microbiolspec May 2016 vol. 4 no. 3 doi:10.1128/microbiolspec.VMBF-0024-2015
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Type IV secretion system (T4SS) effectors and cellular consequences of translocation by intracellular pathogens. The pathogens listed deliver effector proteins to establish a replicative niche within phagosomal compartments. Associated with each organism is the name of the T4SS, the replicative niche (e.g., LCV for -containing vacuole), the host cell type(s) targeted, and the current number of known or estimated effectors. Also for each organism is a list of representative effectors and cellular consequences of their activity within the host cell (colored boxes).

Source: microbiolspec May 2016 vol. 4 no. 3 doi:10.1128/microbiolspec.VMBF-0024-2015
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Type IV secretion systems and disease manifestations

Source: microbiolspec May 2016 vol. 4 no. 3 doi:10.1128/microbiolspec.VMBF-0024-2015
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T4SS machine adaptations enabling specialized functions

Source: microbiolspec May 2016 vol. 4 no. 3 doi:10.1128/microbiolspec.VMBF-0024-2015
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Molecular mimicry: eukaryotic protein domains carried by T4SS effectors

Source: microbiolspec May 2016 vol. 4 no. 3 doi:10.1128/microbiolspec.VMBF-0024-2015

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