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  • Review Article
  • Published:

Exit strategies of intracellular pathogens

Nature Reviews Microbiology volume 6, pages 99–110 (2008)Cite this article

Key Points

  • How intracellular pathogens exit host cells is an important and overlooked topic in the study of host–pathogen interactions.

  • This Review highlights the diverse strategies and specialized mechanisms that are used by intracellular pathogens to escape their resident vacuole and, subsequently, the host cell.

  • Vacuole exit is typically accomplished by the action of pathogen-secreted pore-forming proteins, or phospholipases, on vacuole membranes to cause their disruption.

  • Strategies for pathogen exit from cells include: triggering host-cell lysis from within the cell; using actin-based motility to protrude out of the host cell; budding out of the cell; vacuole extrusion out of the cell; vacuole exocytosis; induction of inflammatory pyroptosis in the host cell; and induction of host-cell apoptosis.

Abstract

The exit of intracellular pathogens from host cells is an important step in the infectious cycle, but is poorly understood. It has recently emerged that microbial exit is a process that can be directed by organisms from within the cell, and is not simply a consequence of the physical or metabolic burden that is imposed on the host cell. This Review summarizes our current knowledge on the diverse mechanisms that are used by intracellular pathogens to exit cells. An integrated understanding of the diversity that exists for microbial exit pathways represents a new horizon in the study of host–pathogen interactions.

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Figure 1: Mechanisms of vacuole escape by intracellular pathogens.
Figure 2: Vacuole escape into the cytosol by Listeria monocytogenes under different invasion conditions.
Figure 3: Strategies and mechanisms used by intracellular pathogens to exit host cells.
Figure 4: Examples of bacterial exit mechanisms.

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Acknowledgements

The authors thank D. Portnoy, P. Sansonetti, R. Vance and C. Conant for providing a critical review and comments regarding the manuscript.

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Authors and Affiliations

  1. Division of Infectious Diseases, School of Public Health, University of California, Berkeley, 94720, California, USA

    Kevin Hybiske & Richard S. Stephens

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  1. Kevin Hybiske
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  2. Richard S. Stephens
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Correspondence to Richard S. Stephens.

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DATABASES

Entrez Genome Project

Burkholderia pseudomallei

Chlamydia trachomatis

Chlamydia pneumoniae

Cryptococcus neoformans

Francisella tularensis

Legionella pneumophila

Listeria monocytogenes

Mycobacterium marinum

Orientia tsutsugamushi

Plasmodium berghei

Plasmodium falciparum

Rickettsia conorii

Rickettsia prowazekii

Rickettsia rickettsii

Rickettsia typhi

Salmonella typhimurium

Shigella flexneri

Toxoplasma gondii

Trypanosoma cruzi

Entrez Protein

IpaB

IpaC

IpaD

VirA

FURTHER INFORMATION

Richard S. Stephens's homepage

Glossary

Pore-forming protein

(PFP). A secreted protein that inserts into and disrupts membrane bilayers by forming pores that are permeable to ions and macromolecules.

Osmotic lysis

The consequence of the cytosol becoming hypertonic to the extracellular environment; results in water influx, cell swelling and membrane rupture.

Secondary vacuole

A double-membrane vacuole that is formed after the cell-to-cell spread of some actin-motile bacteria. The inner and outer membranes are derived from the plasma membrane's initial and target host cells, respectively.

Obligate intracellular parasite

A pathogen that is capable only of replicative growth within host cells.

Actin-related protein 2/3 complex

A seven-subunit protein complex that is activated in response to actin-nucleation promoting factors, to directly initiate actin polymerization into y-branched actin networks.

Necrosis

Cell death that is generally due to environmental insults or physical damage that is incurred by the cell. Necrosis is morphologically characterized by extensive membrane destruction.

Type III secretion system

(T3SS). A needle-like secretion apparatus in Gram-negative bacteria that forms pores in host membranes and allows the injection of virulence factors from the bacterial cytoplasm into the cytosol of host cells.

Pathogen-associated molecular pattern

A small molecular motif that is conserved across microbial species and engages innate immune receptors (for example, Toll-like receptors). Examples include: lipopolysaccharide, peptidoglycan, flagellin, double stranded RNA and unmethylated cytosine phosphate guanosine DNA motifs.

Pathogenicity island

A large genomic insertion that is acquired by horizontal transfer and contains numerous genes that are associated with virulence.

Flagellin

A subunit protein in flagella structures in bacteria; also recognized by the host innate immune system.

Dot–Icm type IV secretion system

A multi-protein secretion system in L. pneumophila that is used to secrete virulence factors into the cytosol of host cells, and is essential for intracellular infection.

Polymorphonuclear lymphocyte

A class of leukocytes that includes neutrophils, eosinophils and basophils, and is characterized by the possession of multi-lobed nuclei.

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Hybiske, K., Stephens, R. Exit strategies of intracellular pathogens. Nat Rev Microbiol 6, 99–110 (2008). https://doi.org/10.1038/nrmicro1821

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