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Manipulation of Host Cell Organelles by Intracellular Pathogens

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  • Authors: Titilayo O. Omotade1, Craig R. Roy2
  • Editors: Pascale Cossart3, Craig R. Roy4, Philippe Sansonetti5
  • VIEW AFFILIATIONS HIDE AFFILIATIONS
    Affiliations: 1: Department of Microbial Pathogenesis, Yale University, New Haven, CT; 2: Department of Microbial Pathogenesis, Yale University, New Haven, CT; 3: Institut Pasteur, Paris, France; 4: Yale University School of Medicine, New Haven, Connecticut; 5: Institut Pasteur, Paris, France
  • Source: microbiolspec April 2019 vol. 7 no. 2 doi:10.1128/microbiolspec.BAI-0022-2019
  • Received 10 January 2019 Accepted 28 January 2019 Published 26 April 2019
  • Craig R. Roy, [email protected]
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  • Abstract:

    In this article, we explore the unique adaptations of intracellular bacterial pathogens that manipulate conserved cellular pathways, organelles, and cargo to convert the phagosome into a pathogen-containing vacuole (PCV). The phagosome is a degradative organelle that rapidly acidifies as it delivers cargo to the lysosome to destroy microbes and cellular debris. However, to avoid this fate, intracellular bacterial pathogens hijack the key molecular modulators of intracellular traffic: small GTPases, phospholipids, SNAREs, and their associated effectors. Following uptake, pathogens that reside in the phagosome either remain associated with the endocytic pathway or rapidly diverge from the preprogrammed route to the lysosome. Both groups rely on effector-mediated mechanisms to meet the common challenges of intracellular life, such as nutrient acquisition, vacuole expansion, and evasion of the host immune response. , , and serve as a lens through which we explore regulators of the canonical endocytic route and pathogens that seek to subvert it. On the other hand, pathogens such as , , and disconnect from the canonical endocytic route. This bifurcation is linked to extensive hijacking of the secretory pathway and repurposing of the PCV into specialized compartments that resemble organelles in the secretory network. Finally, each pathogen devises specific strategies to counteract host immune responses, such as autophagy, which aim to destroy these aberrant organelles. Collectively, each unique intracellular niche and the pathogens that construct them reflect the outcome of an aggressive and ongoing molecular arms race at the host-pathogen interface. Improving our understanding of these well-adapted pathogens can help us refine our knowledge of conserved cell biological processes.

  • Citation: Omotade T, Roy C. 2019. Manipulation of Host Cell Organelles by Intracellular Pathogens. Microbiol Spectrum 7(2):BAI-0022-2019. doi:10.1128/microbiolspec.BAI-0022-2019.

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/content/journal/microbiolspec/10.1128/microbiolspec.BAI-0022-2019
2019-04-26
2019-09-22

Abstract:

In this article, we explore the unique adaptations of intracellular bacterial pathogens that manipulate conserved cellular pathways, organelles, and cargo to convert the phagosome into a pathogen-containing vacuole (PCV). The phagosome is a degradative organelle that rapidly acidifies as it delivers cargo to the lysosome to destroy microbes and cellular debris. However, to avoid this fate, intracellular bacterial pathogens hijack the key molecular modulators of intracellular traffic: small GTPases, phospholipids, SNAREs, and their associated effectors. Following uptake, pathogens that reside in the phagosome either remain associated with the endocytic pathway or rapidly diverge from the preprogrammed route to the lysosome. Both groups rely on effector-mediated mechanisms to meet the common challenges of intracellular life, such as nutrient acquisition, vacuole expansion, and evasion of the host immune response. , , and serve as a lens through which we explore regulators of the canonical endocytic route and pathogens that seek to subvert it. On the other hand, pathogens such as , , and disconnect from the canonical endocytic route. This bifurcation is linked to extensive hijacking of the secretory pathway and repurposing of the PCV into specialized compartments that resemble organelles in the secretory network. Finally, each pathogen devises specific strategies to counteract host immune responses, such as autophagy, which aim to destroy these aberrant organelles. Collectively, each unique intracellular niche and the pathogens that construct them reflect the outcome of an aggressive and ongoing molecular arms race at the host-pathogen interface. Improving our understanding of these well-adapted pathogens can help us refine our knowledge of conserved cell biological processes.

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Image of FIGURE 1
FIGURE 1

Rab GTPase signature of PCVs that interact with the endocytic pathway. The figure depicts canonical phagocytosis, with a subset of intracellular pathogens that manipulate endosomal traffic to avoid lysosomal degradation. When professional phagocytes recognize bacteria, local rearrangement of the actin cytoskeleton allows the plasma membrane to form protrusions that engulf bacterial cells into a host-derived membrane called the phagosome. Nascent phagosomes transiently interact with early and late endosomes to convert this compartment into an acidic and microbicidal organelle. The early-endosomal marker Rab5 associates with newly formed phagosomes, and as maturation progresses, Rab5 is displaced by the late-endosomal marker Rab7. This process culminates with lysosomal fusion, which generates a hybrid organelle called the phagolysosome that promotes complete degradation of phagocytosed bacteria. Following uptake, interacts with early endosomes but immediately stalls maturation to avoid acidification of the MCV. suspends normal transit along the endocytic route by interfering with the conversion of Rab5 to Rab7 on the MCV membrane. Consequently, by arresting the development of phagosomes during early stages of uptake, the MCV retains features of an early-endosome-like compartment and avoids delivery to the lysosome. Additionally, Rab22a and Rab14 have been detected on vacuoles. In contrast, the SCV transits further down the endocytic route and interacts with both early and late endosomes. The conventional (early- and late-endosome) Rab GTPases Rab5 and Rab7 localize to mature SCVs along with the late-endosome marker LAMP-1/2. Mature SCVs are dynamic compartments that closely resemble late endosomes. Unlike and , does not resist delivery to the lysosome. vacuoles progress along the standard endocytic route in a process that closely resembles canonical phagocytosis, and these compartments display many markers that associate with mature phagosomes, such as Rab5, Rab7, and LAMP-1. Delivery to the lysosome activates the T4SS machinery and triggers effector-mediated mechanisms that drastically alter properties of the lysosome and support biogenesis of the CCV. repurposes the lysosome into a phenotypically distinct lysosome-derived organelle that participates in unregulated fusion events in an autophagy-dependent manner. Interestingly, additional Rab GTPases that have been linked to the autophagy pathway, Rab1 and Rab24, have been shown to contribute to replication.

Source: microbiolspec April 2019 vol. 7 no. 2 doi:10.1128/microbiolspec.BAI-0022-2019
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Image of FIGURE 2
FIGURE 2

Rab GTPase signature of PCVs that diverge from the endocytic pathway and manipulate the pathway. The figure depicts a class of intracellular pathogens that not only avoid lysosomal degradation but also disconnect from the standard endocytic route and extensively manipulate secretory traffic. Once internalized, these pathogens manipulate Rab GTPases to create a unique molecular signature on the phagosomal membrane. Consequently, this signature rewrites the function of the original phagosome and allows each pathogen to exploit host membrane transport of secretory organelles (ER and Golgi apparatus) and their associated vesicles. As such, the atypical recruitment and association of Rab GTPases on each PCV membrane provides insight into the organelles that are hijacked and exploited for PCV biogenesis and maintenance. The -containing phagosome disassociates from the endocytic pathway very early after uptake, as the early-endosome marker Rab5 is not detected on this compartment. However, Rab1, an ER-associated Rab GTPase, is recruited to the -containing vacuole (LCV) following internalization. The localization of activated Rab1 on the LCV membrane allows this pathogen to hijack ER-derived vesicles and redirect them to the LCV surface. As the infection proceeds, the LCV matures into a ribosome-studded organelle that communicates extensively with the ER. Similar to , remodels the phagosome into an ER-like organelle. In contrast, the BCV does not acquire Rab1 to hijack vesicles from ERES. Instead, the recruitment of Rab2 to the BCV is required to subvert ER-Golgi traffic and support BCV biogenesis. is initially phagocytosed as an elementary body (EB), which represents the metabolically inactive and infectious form of the biphasic cycle. As the infection progresses, the EB differentiates into the metabolically active and replicative form termed the reticulate body (RB). The specialized organelle that supports replication, named the inclusion, is largely devoid of endocytic Rabs, including Rab5, Rab7, and Rab9. This indicates that divergence from the endocytic route is an early and rapid event. A wide assortment of Rab GTPases are recruited to the inclusion membrane, such as Rab1, Rab4, Rab6, Rab11, and Rab14. A hallmark of intracellular infection is the presence of fragmented Golgi stacks that surround the inclusion.

Source: microbiolspec April 2019 vol. 7 no. 2 doi:10.1128/microbiolspec.BAI-0022-2019
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