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The Role of the Type III Secretion System in the Intracellular Lifestyle of Enteric Pathogens

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  • Authors: Marcela De Souza Santos1, Kim Orth2
  • Editors: Pascale Cossart5, Craig R. Roy6, Philippe Sansonetti7
  • VIEW AFFILIATIONS HIDE AFFILIATIONS
    Affiliations: 1: Department of Molecular Biology, University of Texas Southwestern Medical Center, Dallas, TX 75390; 2: Department of Molecular Biology, University of Texas Southwestern Medical Center, Dallas, TX 75390; 3: Department of Biochemistry and; 4: Howard Hughes Medical Institute, University of Texas Southwestern Medical Center, Dallas, TX 75390; 5: Institut Pasteur, Paris, France; 6: Yale University School of Medicine, New Haven, Connecticut; 7: Institut Pasteur, Paris, France
  • Source: microbiolspec May 2019 vol. 7 no. 3 doi:10.1128/microbiolspec.BAI-0008-2019
  • Received 19 April 2018 Accepted 15 February 2019 Published 31 May 2019
  • Kim Orth, [email protected]
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  • Abstract:

    Several pathogens have evolved to infect host cells from within, which requires subversion of many host intracellular processes. In the case of Gram-negative pathogenic bacteria, adaptation to an intracellular life cycle relies largely on the activity of type III secretion systems (T3SSs), an apparatus used to deliver effector proteins into the host cell, from where these effectors regulate important cellular functions such as vesicular trafficking, cytoskeleton reorganization, and the innate immune response. Each bacterium is equipped with a unique suite of these T3SS effectors, which aid in the development of an individual intracellular lifestyle for their respective pathogens. Some bacteria adapt to reside and propagate within a customized vacuole, while others establish a replicative niche in the host cytosol. In this article, we review the mechanisms by which T3SS effectors contribute to these different lifestyles. To illustrate the formation of a vacuolar and a cytosolic lifestyle, we discuss the intracellular habitats of the enteric pathogens serovar Typhimurium and , respectively. These represent well-characterized systems that function as informative models to contribute to our understanding of T3SS-dependent subversion of intracellular processes. Additionally, we present , another enteric Gram-negative pathogen, as an emerging model for future studies of the cytosolic lifestyle.

  • Citation: De Souza Santos M, Orth K. 2019. The Role of the Type III Secretion System in the Intracellular Lifestyle of Enteric Pathogens. Microbiol Spectrum 7(3):BAI-0008-2019. doi:10.1128/microbiolspec.BAI-0008-2019.

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/content/journal/microbiolspec/10.1128/microbiolspec.BAI-0008-2019
2019-05-31
2019-06-18

Abstract:

Several pathogens have evolved to infect host cells from within, which requires subversion of many host intracellular processes. In the case of Gram-negative pathogenic bacteria, adaptation to an intracellular life cycle relies largely on the activity of type III secretion systems (T3SSs), an apparatus used to deliver effector proteins into the host cell, from where these effectors regulate important cellular functions such as vesicular trafficking, cytoskeleton reorganization, and the innate immune response. Each bacterium is equipped with a unique suite of these T3SS effectors, which aid in the development of an individual intracellular lifestyle for their respective pathogens. Some bacteria adapt to reside and propagate within a customized vacuole, while others establish a replicative niche in the host cytosol. In this article, we review the mechanisms by which T3SS effectors contribute to these different lifestyles. To illustrate the formation of a vacuolar and a cytosolic lifestyle, we discuss the intracellular habitats of the enteric pathogens serovar Typhimurium and , respectively. These represent well-characterized systems that function as informative models to contribute to our understanding of T3SS-dependent subversion of intracellular processes. Additionally, we present , another enteric Gram-negative pathogen, as an emerging model for future studies of the cytosolic lifestyle.

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Figures

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FIGURE 1

Schematic of the contribution of T3SS effectors to the intracellular lifecycle of Typhimurium . Following invasion of epithelial cells, Typhimurium employs the effectors SopE/E2 and SopB to transiently recruit early endosomal markers to the -containing vacuole (SCV) . SCV maturation and acquisition of Rab7 lead to dynein-mediated translocation of this vacuole to the host cell perinuclear region . Development of the SCV into a bactericidal compartment is precluded by the action of SopB, GtgE, and SopD2, which collectively, inhibit the endosomal-lysosomal fusion activities of Rab35, Rab32, and Rab7. SseF and SseG, in complex with GCP60/ACBD3, maintain the SCV juxtanuclear position. Additionally, SifA, through its eukaryotic effector SKIP, inhibits PipB2/kinesin-1-mediated centrifugal movement of the SCV . Next, the SCV develops Sifs, which coincides with the onset of Typhimurium intravacuolar replication. Sif formation is the product of the concerted action of SifA, PipB2, and SseJ. SifA and PipB2 coordinate the centrifugal extension of the Sifs, while SifA and SseJ regulate SCV and Sif membrane dynamics that support Sif growth. Filament growth is further promoted by SptP . The SCV is surrounded by an actin meshwork which contributes to maintaining SCV integrity. The effectors SipA, SpvB, and SteC modulate actin dynamics in the surroundings of the SCV.

Source: microbiolspec May 2019 vol. 7 no. 3 doi:10.1128/microbiolspec.BAI-0008-2019
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Image of FIGURE 2
FIGURE 2

Schematic of the contribution of virulence factors to the intracellular lifecycle of . briefly resides within its entry vacuole (CV) . The CV is ruptured by the pore-forming activity of the T3SS translocon proteins IpaB and IpaC. IpgD facilitates vacuolar disruption by generating Rab11-macropinosomes that fuse to . Upon rupture of the CV, escapes into the host cytosol, from where the bacterium employs its IcsA to recruit actin cytoskeleton machinery, namely, N-WASP and Arp2/3 that polymerize actin filaments at one pole of the bacterium . Unidirectional actin polymerization propels the bacterium across the host cytosol, leading to protrusions that enable bacterial spread into the neighboring cell . In the secondary cell, is initially contained within a double-membrane vacuole (protrusion CV) . Recruitment of LC3 to the protrusion vacuole is controlled by the T3SS effector VirA, which targets the Rho GTPase Rab1 . IpaB, IpaC, and the T3SS effector IcsB promote bacterial escape from the protrusion of CV into the cytosol, enabling the bacterium to complete another infection cycle.

Source: microbiolspec May 2019 vol. 7 no. 3 doi:10.1128/microbiolspec.BAI-0008-2019
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FIGURE 3

Schematic of the intracellular lifecycle and the T3SS effectors that contribute to it . The T3SS2 effector VopC induces epithelial host cell plasma membrane ruffling that internalizes into a nascent vacuole. The nascent vacuole develops first into an early endosome-like compartment, given by its acquisition of EEA1 and subsequently matures into a late endosome-like vacuole, given by the recruitment of Lamp-1 . The bacterium disrupts its containing vacuole and escapes into the cytosol, where bacterial replication takes place . To evade host immune defenses, employs the T3SS2 VopL, which disrupts the actin cytoskeleton and thereby inhibits the actin-dependent assembly of the ROS-producing NADPH oxidase complex.

Source: microbiolspec May 2019 vol. 7 no. 3 doi:10.1128/microbiolspec.BAI-0008-2019
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Tables

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TABLE 1

SPI-1 and SPI-2 effectors that contribute to the intracellular lifecycle of Typhimurium

Source: microbiolspec May 2019 vol. 7 no. 3 doi:10.1128/microbiolspec.BAI-0008-2019
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TABLE 2

Virulence factors that contribute to the intracellular lifecycle of

Source: microbiolspec May 2019 vol. 7 no. 3 doi:10.1128/microbiolspec.BAI-0008-2019

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