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  • Review Article
  • Published:

Targeting of host organelles by pathogenic bacteria: a sophisticated subversion strategy

Nature Reviews Microbiology volume 14, pages 5–19 (2016)Cite this article

Subjects

Key Points

  • Pathogenic bacteria evade host defences by subverting host signalling pathways in many different and sophisticated ways. An intriguing strategy used by several pathogens, mainly intracellular bacteria, is molecular or structural mimicry of host proteins.

  • In the past few years, studies have revealed that some pathogenic bacteria secret specific proteins via their type 3 secretion systems (T3SSs) and type 4 secretion systems (T4SSs) to target host organelles. These proteins contain organelle localization signals that target the effectors, for example to the nucleus or the mitochondria.

  • Legionella pneumophila, Chlamydia trachomatis and Burkholderia thailandensis secrete SET domain-containing proteins that encode histone methyltransferase activity to directly impose epigenetic changes on the chromatin landscape of the host cell, thus aiding bacterial intracellular replication.

  • Listeria monocytogenes, pathogenic Escherichia coli strains and Shigella flexneri secrete specific effector proteins that change the levels of chromatin-binding proteins to indirectly alter the host chromatin to the advantage of the pathogen.

  • Membrane dynamics, and in particular the eukaryotic secretory pathway, are targeted by bacterial pathogens to allow them to form a distinct replication-permissive vacuole inside the host cell. Legionella spp. and Brucella spp. target endoplasmic reticulum (ER)-derived vesicles and the retrograde traffic between the Golgi and the ER; Salmonella spp. and Chlamydia spp. interact with the trans-Golgi network or associated compartments.

  • To target the ER or Golgi network, different secreted effectors evolved to specifically hijack RAB proteins and exploit phosphoinositide lipids, which are phosphorylated derivatives of phosphatidylinositol.

  • Mitochondria are the power plants of the cell, but are also involved in essential cellular processes such as programmed cell death, calcium homeostasis, and the biosynthesis of amino acids, lipids and nucleotides. They also serve as hubs for innate immune signalling against viruses and bacteria.

  • L. pneumophila, enteropathogenic E. coli, Vibrio cholerae and Anaplasma phagocytophilum have been reported to secrete diverse effectors that target mitochondria, mainly to inhibit inflammatory responses.

Abstract

Many bacterial pathogens have evolved the ability to subvert and exploit host functions in order to enter and replicate in eukaryotic cells. For example, bacteria have developed specific mechanisms to target eukaryotic organelles such as the nucleus, the mitochondria, the endoplasmic reticulum and the Golgi apparatus. In this Review, we highlight the most recent advances in our understanding of the mechanisms that bacterial pathogens use to target these organelles. We also discuss how these strategies allow bacteria to manipulate host functions and to ultimately enable bacterial infection.

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Figure 1: Eukaryotic organelles targeted by pathogenic bacteria.
Figure 2: Nuclear targeting by bacterial effectors.
Figure 3: Endoplasmic reticulum and Golgi targeting by bacterial effectors.
Figure 4: Mitochondrial targeting by bacterial effectors.

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Acknowledgements

The authors thank S. Gordon for critical reading of the manuscript. Work in the C.B. laboratory is financed by the Institut Pasteur, the Institut Carnot Pasteur Maladies Infectieuses, the French Region Ile de France (through the DIM Malinf programme) and the Infect-ERA project EUGENPATH (grant ANR-13-IFEC-0003-02). S.M. is financed by the French Agence Nationale de la Recherche (grant ANR-10-LABX- 62-IBEID). P.E. is funded by the Fondation pour la Recherche Médicale (grant DEQ20120323697).

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  1. Biologie des Bactéries Intracellulaires, Centre National de la Recherche Scientifique UMR 3525, Institut Pasteur, Biologie des 28 rue du Dr. Roux, Paris Cedex 15, 75724, France

    Pedro Escoll, Sonia Mondino, Monica Rolando & Carmen Buchrieser

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  1. Pedro Escoll
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  2. Sonia Mondino
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  3. Monica Rolando
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PowerPoint slides

Glossary

Effector proteins

Bacterial proteins that are translocated by specific secretion systems into the eukaryotic host cell to promote the survival and replication of the pathogen by modulating the host response.

Secretion systems

Macromolecular structures that deliver proteins or DNA across the cell membrane in bacteria. Seven secretion systems have been identified to date (types 1 through 7). In particular, type 3 secretion systems and type 4 secretion systems inject effector molecules into the cytosol of eukaryotic host cells to manipulate host functions to the pathogen's advantage.

Horizontal gene transfer

(HGT). The transmission of DNA between different genomes of prokaryotes and/or eukaryotes, or between the three DNA-containing organelles of eukaryotes (the nucleus, the mitochondrion and the chloroplast).

Ubiquitin pathway

A reversible post-translational modification pathway involving an enzymatic cascade in which three different enzymes activate, transfer and link ubiquitin on the target protein. This common process of ubiquitylation occurs in a wide range of cell signalling pathways in eukaryotes; one of the most common is the targeting of a protein to the proteasome, in which ubiquitin conjugation is a signal for hydrolysis.

Localization signals

Protein motifs that target proteins to specific compartments within the cell, such as the nucleus or the mitochondria.

Pathogen-associated molecular patterns

(PAMPs). Structurally conserved molecules that are common to all pathogens and are recognized by host pattern recognition receptors (PRRs) to drive immune responses. Examples are microbial products such as lipopolysaccharide, lipoteichoic acid and flagellin.

Histone deacetylases

(HDACs). Specialized enzymes that remove the acetyl group from the lysine residues of histones.

Interferon-stimulated genes

(ISGs).Genes harbouring promoters that are responsive to interferons, a group of signalling proteins made and released by host cells in response to the presence of pathogens.

Apoptosis

A type of programmed cell death in which the cell dies without causing inflammatory reactions.

Histone acetyltransferase

(HAT). An enzyme that catalyses the addition of an acetyl group to the lysine residues of histones. This neutralizes the positive charge of the amino group of the lysine side chain, thereby promoting gene expression.

Elementary body

(EB). The infectious, extracellular form of Chlamydia spp. The EB possesses reduced metabolic activity and is unable to divide. This is the form released after disruption of infected cells.

Reticulate body

(RB). The non-infectious, intracellular form of Chlamydia spp. The RB is a replicative form that actively divides and is unable to initiate a new infection cycle.

Ribosomal DNA

(rDNA). The DNA sequence that encodes rRNA, which participates in protein synthesis.

Anterograde trafficking

A membrane-trafficking pathway in which a linear assembly of membrane-bound compartments facilitates cargo movement from the endoplasmic reticulum towards the cell surface.

Retrograde Golgi–ER transport

The trafficking of vesicles in a direction that starts from the host cell surface and ends in the endoplasmic reticulum (ER).

Legionella-containing vacuole

(LCV). A plasma membrane-derived organelle that avoids maturation into a phagosome, providing a niche wherein Legionella spp. replicate.

AMPylation

The covalent transfer of an AMP moiety from ATP to a hydroxyl side-chain of a protein (at threonine or tyrosine residues); this alters the activity of the protein.

Brucella-containing vacuole

(BCV). A membrane-bound compartment wherein intracellular Brucella spp. reside and multiply.

Chlamydial inclusion

An intracellular membrane-enclosed organelle that supports the intracellular growth of Chlamydia spp.

Salmonella-containing vacuole

(SCV). A membrane-bound compartment wherein intracellular Salmonella spp. reside and multiply. The SCV undergoes various surface modifications that distinguish it morphologically.

Salmonella-induced filaments

(SIFs). Tubules that are induced by infection with Salmonella spp. and are enriched in host late-endocytic proteins, such as LAMP1, and Salmonella pathogenicity island 2 (SPI-2) effectors.

Mitochondrial membrane potential

(Δψm). The potential generated by the mitochondrial electron transport chain, which drives a proton flow from the matrix through the inner mitochondrial membrane. As the proton concentration increases in the intermembrane space, a strong electrochemical gradient is established across the inner membrane. This gradient is used by the ATP synthase complex to produce ATP via oxidative phosphorylation.

Dominant-negative phenotype

A phenotype caused by a mutation of a gene or the expression of a protein that cannot be rescued by the wild-type genotype.

Pilus

A hair-like appendage present on the surface of many bacteria. Pili are polymers of pilin subunits and are essential for virulence of many bacteria, as they mediate a wide range of functions, including motility, microcolony and biofilm formation, and immune escape.

MAVS

(Mitochondrial antiviral-signalling protein). A protein that is localized in the mitochondrial outer membrane and aggregates after cytoplasmic detection of viral or bacterial RNA, leading to the production of interferons and other pro-inflammatory cytokines by the infected cell.

Autophagosome

A double-membraned vesicle, formed from small membrane structures, that engulfs undesirable cellular components or organelles, including invading microorganisms. After their formation, autophagosomes deliver their contents to the lysosomes, where hydrolases degrade both the contents and the autophagosome inner membrane.

Autophagy

A catabolic process by which the eukaryotic cell degrades undesirable or dysfunctional cellular components. It promotes cellular survival during starvation by maintaining cellular energy levels. When the cellular autophagy machinery is used to remove intracellular pathogens, the process is called xenophagy.

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Escoll, P., Mondino, S., Rolando, M. et al. Targeting of host organelles by pathogenic bacteria: a sophisticated subversion strategy. Nat Rev Microbiol 14, 5–19 (2016). https://doi.org/10.1038/nrmicro.2015.1

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