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Cellular Exit Strategies of Intracellular Bacteria

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  • Authors: Kevin Hybiske1, Richard Stephens2
  • Editors: Indira T. Kudva3, John P. Bannantine4
  • VIEW AFFILIATIONS HIDE AFFILIATIONS
    Affiliations: 1: Division of Allergy and Infectious Diseases, Department of Medicine, University of Washington, Seattle, WA 98195; 2: Program in Infectious Diseases, School of Public Health, University of California, Berkeley, Berkeley, CA 94720; 3: National Animal Disease Center, Agricultural Research Service, U.S. Department of Agriculture, Ames, IA; 4: National Animal Disease Center, Agricultural Research Service, U.S. Department of Agriculture, Ames, IA
  • Source: microbiolspec December 2015 vol. 3 no. 6 doi:10.1128/microbiolspec.VMBF-0002-2014
  • Received 10 December 2014 Accepted 14 April 2015 Published 18 December 2015
  • Richard Stephens, rss@berkeley.edu
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  • Abstract:

    The coevolution of intracellular bacteria with their eukaryotic hosts has presented these pathogens with numerous challenges for their evolutionary progress and survival. Chief among these is the ability to exit from host cells, an event that is fundamentally linked to pathogen dissemination and transmission. Recent years have witnessed a major expansion of research in this area, and this chapter summarizes our current understanding of the spectrum of exit strategies that are exploited by intracellular pathogens. Clear themes regarding the mechanisms of microbial exit have emerged and are most easily conceptualized as (i) lysis of the host cell, (ii) nonlytic exit of free bacteria, and (iii) release of microorganisms into membrane-encased compartments. The adaptation of particular exit strategies is closely linked with additional themes in microbial pathogenesis, including host cell death, manipulation of host signaling pathways, and coincident activation of proinflammatory responses. This chapter will explore the molecular determinants used by intracellular pathogens to promote host cell escape and the infectious advantages each exit pathway may confer, and it will provide an evolutionary framework for the adaptation of these mechanisms.

  • Citation: Hybiske K, Stephens R. 2015. Cellular Exit Strategies of Intracellular Bacteria. Microbiol Spectrum 3(6):VMBF-0002-2014. doi:10.1128/microbiolspec.VMBF-0002-2014.

Key Concept Ranking

Bacterial Proteins
0.5847813
Type IV Secretion System Proteins
0.4192028
Type III Secretion System Proteins
0.40793023
0.5847813

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/content/journal/microbiolspec/10.1128/microbiolspec.VMBF-0002-2014
2015-12-18
2017-03-27

Abstract:

The coevolution of intracellular bacteria with their eukaryotic hosts has presented these pathogens with numerous challenges for their evolutionary progress and survival. Chief among these is the ability to exit from host cells, an event that is fundamentally linked to pathogen dissemination and transmission. Recent years have witnessed a major expansion of research in this area, and this chapter summarizes our current understanding of the spectrum of exit strategies that are exploited by intracellular pathogens. Clear themes regarding the mechanisms of microbial exit have emerged and are most easily conceptualized as (i) lysis of the host cell, (ii) nonlytic exit of free bacteria, and (iii) release of microorganisms into membrane-encased compartments. The adaptation of particular exit strategies is closely linked with additional themes in microbial pathogenesis, including host cell death, manipulation of host signaling pathways, and coincident activation of proinflammatory responses. This chapter will explore the molecular determinants used by intracellular pathogens to promote host cell escape and the infectious advantages each exit pathway may confer, and it will provide an evolutionary framework for the adaptation of these mechanisms.

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Figures

Image of FIGURE 1
FIGURE 1

Pore-forming proteins mediate the exit of . Exit signals for originate within the parasite and consist of elevations in abscisic acid (ABA) leading to increases in intraparasite calcium concentrations. Calcium spikes induce protein secretion by rhoptry organelles, including the pore-forming protein TgPLP1. Insertion of PLP1 in the vacuole membrane causes its disruption, and PLP1 insertion in the host plasma membrane causes further disruption of ionic gradients, including potassium. Host calpains are also activated during this process, and they play key roles in degrading cytoskeletal proteins and complexes that are normally important for maintaining vacuole membrane integrity. Successful exit of parasites is accomplished by penetration of motile parasites through these weakened membranes.

Source: microbiolspec December 2015 vol. 3 no. 6 doi:10.1128/microbiolspec.VMBF-0002-2014
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Image of FIGURE 2
FIGURE 2

Lysis of -infected cells by cysteine proteases. Cysteine proteases are activated at late stages of developmental growth in cells; protease identities are unknown but may be bacterial, host, or both. Cysteine protease activity is required to degrade proteins essential for maintaining vacuole integrity. The secreted chlamydial serine protease CPAF plays a role in degradation of intermediate filaments that associate with the chlamydial vacuole and may play a role in host cell lysis. After degradation of the vacuole, host nuclei are permeabilized, possibly by cysteine proteases. Lysis of the host plasma membrane is mediated by intracellular calcium signaling, calpain, and potentially additional proteases. Abbreviations: EB, elementary body; RB, reticulate body.

Source: microbiolspec December 2015 vol. 3 no. 6 doi:10.1128/microbiolspec.VMBF-0002-2014
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FIGURE 3

Induction of pyroptosis and host cell lysis by . Once in the cytosol of a host cell, three discrete microbial factors of are capable of activating inflammasomes, subsequent activation of caspase-1, and downstream processing and secretion of IL-1α and IL-18. Flagellin monomers that are sloughed off from flagella trigger activation of the canonical NLRC4 (Nod-like receptor family caspase recruitment domain-containing protein 4) inflammasome. DNA that is released from infrequent lysis of intracellular is recognized by the absent-in-melanoma-2 (AIM2) inflammasome. Listeriolysin O (LLO), the pore-forming protein secreted by , is capable of activating the NLRP3 inflammasome. Pyroptosis leads to host cell death and the release of from the host cell.

Source: microbiolspec December 2015 vol. 3 no. 6 doi:10.1128/microbiolspec.VMBF-0002-2014
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FIGURE 4

Activation of intrinsic apoptosis and host cell death by . Intracellular is capable of activating the intrinsic pathway of apoptosis in host cells. The microbial factors of that induce apoptosis signaling have not been identified; however, infection results in cytochrome c release from mitochondria, followed by caspase-9 and caspase-3 activation. Ultimately, cellular substrates are cleaved by caspases, and host membranes bleb into apoptotic bodies which may contain bacteria. Whether , or other bacteria that trigger apoptotic death, reside exclusively in apoptotic bodies or if they have free access to the extracellular space upon host death is unclear.

Source: microbiolspec December 2015 vol. 3 no. 6 doi:10.1128/microbiolspec.VMBF-0002-2014
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Image of FIGURE 5
FIGURE 5

Exit of from amoeba by exocytosis. From inside a vacuole of an infected amoeboid host, secretes two known effector proteins into the host cytosol, LepA and LepB, which are directly responsible for promoting the fusion of the -containing vacuole with the amoeba plasma membrane. This exocytic process results in the free release of bacteria into the extracellular space and leaves the host cell intact. Both effector proteins are secreted by the Icm/Dot type IV secretion system, and thereafter they are recruited to the vacuole membrane.

Source: microbiolspec December 2015 vol. 3 no. 6 doi:10.1128/microbiolspec.VMBF-0002-2014
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Image of FIGURE 6
FIGURE 6

Ejection of from amoeba. Through a mechanism that requires myosin IB coronin, and type VII secreted protein(s) by the bacteria, can induce the formation of an actin barrel-like structure on the amoeba plasma membrane. Through this large pore-like structure, can traverse the cell membrane and exit from the cell. Although permeability is transiently formed on the amoeba membrane, it reseals to keep the host cell intact after the event is completed.

Source: microbiolspec December 2015 vol. 3 no. 6 doi:10.1128/microbiolspec.VMBF-0002-2014
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FIGURE 7

Extrusion of from host cells. Chlamydial extrusion is a complex process that is orchestrated from bacteria residing in a vacuole. This mechanism consists of a large portion of the bacteria-containing vacuole pinching off and releasing from the host cell. The host cell remains intact upon completion of this exit strategy and can even retain a residual vacuole after the extruded body is released. Extrusion appears to be initiated by unidentified secreted proteins that are secreted across the vacuole membrane and into the host cytosol by type III secretion. Polymerization of nascent actin filaments on the vacuole membrane is required for extrusion formation. The pinching step is mediated by actomyosin contraction and Rho GTPase signaling pathways. A hypothesized contractile ring may form on the vacuole membrane to give rise to the major contraction event that occurs on both the vacuole and host cell. Abbreviations: EB, elementary body; RB, reticulate body.

Source: microbiolspec December 2015 vol. 3 no. 6 doi:10.1128/microbiolspec.VMBF-0002-2014
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FIGURE 8

Actin-based protrusion of . can disseminate to neighboring cells by protruding out of its infected host cell as long filopodia projections and into an adjacent cell. This process is largely derived from mechanisms responsible for the formation of polar actin comet tails on and other bacteria; however, additional molecules are required for actin-based motility to lead to filopodial protrusions. secretes InlC, a protein which binds to the host protein Tuba and sequesters it away from neuronal Wiskott-Aldrich syndrome protein (N-WASP). This results in destabilized cortical actin structures of cell membranes. At these vulnerable membrane regions, protrudes outward into long, membrane-bound filopodia, using Arp2/3- and formin-based actin polymerization as the propulsive force. It is critical for actin tails in protrusions to maintain interactions with the plasma membrane through ezrin and membrane proteins such as CD44.

Source: microbiolspec December 2015 vol. 3 no. 6 doi:10.1128/microbiolspec.VMBF-0002-2014
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Image of FIGURE 9
FIGURE 9

Exit of by budding release. The escape of from host cells is mediated by a budding process that releases individual bacteria out of the cell and encased by host membranes. The underlying molecular mechanisms are poorly understood, but there is evidence that may target lipid raft domains at the plasma membrane as sites for bud formation and egress.

Source: microbiolspec December 2015 vol. 3 no. 6 doi:10.1128/microbiolspec.VMBF-0002-2014
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Tables

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TABLE 1

Lysis exit strategies

Source: microbiolspec December 2015 vol. 3 no. 6 doi:10.1128/microbiolspec.VMBF-0002-2014
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TABLE 2

Cell-free expulsion exit strategies

Source: microbiolspec December 2015 vol. 3 no. 6 doi:10.1128/microbiolspec.VMBF-0002-2014
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TABLE 3

Membrane-encased exit strategies

Source: microbiolspec December 2015 vol. 3 no. 6 doi:10.1128/microbiolspec.VMBF-0002-2014

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