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Chlamydia and apoptosis: life and death decisions of an intracellular pathogen

Key Points

  • The chlamydiae are important obligate intracellular prokaryotic pathogens that replicate in cytoplasmic vesicles in a variety of different eukaryotic host cells, including the mucosal and vascular epithelia, smooth muscle cells, monocytes and macrophages.

  • A key pathogenic strategy of the chlamydiae is the ability to induce host-cell apoptosis under some circumstances and actively inhibit apoptosis under others. This flexible strategy is crucial for the pathogenic success of the chlamydiae as these organisms cause diseases in many different species and in many different host cell types, and a pro-apoptotic response in one host species or cell might not be appropriate in another host species or cell type. Also, the intracellular growth cycle of the chlamydiae is complex and can be productive or non-productive under different growth conditions and the growth status of the bacteria might affect their apoptotic activity.

  • Chlamydia-mediated protection against apoptosis occurs via a variety of different mechanisms. It is thought that Chlamydia trachomatis and Chlamydia pneumoniae can protect infected cells by inhibiting the release of cytochrome c from mitochondria. These chlamydial species also upregulate the expression of the anti-apoptotic mediators IAP and MCL-1. C. pneumoniae infection of monocytes also activates the transcription of NF-κB, although how this transcription factor contributes to the inhibition of apoptosis is still unclear. Protection against apoptosis may be a strategy that the chlamydiae use to maintain a persistent, chronic infection.

  • Chlamydia induction of host cell death has been a recognised phenomenon for more than 30 years, but the mechanisms of this cytotoxicity have only recently begun to be explored. Again, it is likely that different chlamydial species or biovars use different mechanisms and that the same species could use different mechanisms in different host species or cell types. Recent studies have shown that this apoptosis may be caspase independent. A chlamydial protein known as CADD — Chlamydia protein associating with death receptors — was recently identified and it has been suggested that CADD inhibits Fas-mediated apoptosis or induces cell death under different conditions.

Abstract

The chlamydiae are important obligate intracellular prokaryotic pathogens that, each year, are responsible for millions of human infections involving the eye, genital tract, respiratory tract, vasculature and joints. The chlamydiae grow in cytoplasmic vesicles in susceptible host cells, which include the mucosal epithelium, vascular endothelium, smooth muscle cells, circulating monocytes and recruited or tissue-specific macrophages. One important pathogenic strategy that chlamydiae have evolved to promote their survival is the modulation of programmed cell death pathways in infected host cells. The chlamydiae can elicit the induction of host cell death, or apoptosis, under some circumstances and actively inhibit apoptosis under others. This subtle pathogenic mechanism highlights the manner in which these highly successful pathogens take control of infected cells to promote their own survival — even under the most adverse circumstances.

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Figure 1: Infected cells can die through apoptosis or necrosis, or most likely a combination of both.
Figure 2: The chlamydiae have the ability to both activate and inhibit apoptotic signalling pathways in eukaryotic host cells.

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Acknowledgements

Work in the authors' laboratories is supported by grants from the Public Health Service. We thank O. S. Mahdi for her help in organizing and critiquing the manuscript.

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Correspondence to Gerald I. Byrne.

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DATABASES

Entrez

Chlamydia pneuomoniae

Chlamydia psittaci

Chlamydia trachomatis

Mycobacterium tuberculosis

NF-κB

Rickettsia rickettsii

SwissProt

BAK

BAX

BCL-2

BID

BIM

EGR1

EPHA2

HMGB1

IL-10

MCL-1

p53

TGF-β

FURTHER INFORMATION

Gerald I. Byrne's laboratory

David M. Ojcius' laboratory

Glossary

APOPTOSIS

A form of cell death, also known as programmed cell death, which is typically characterized by death receptor ligand or mitochondria-elicited activation of caspase proteases and which leads to nuclear condensation, DNA fragmentation and clearance of the dead cell by surrounding tissue.

CASPASES

Family of cytosolic proteases that contain a cysteine residue within the active site, and which cleave their substrate after an aspartic acid residue. They can be divided into inflammatory caspases, which cleave and activate pro-inflammatory cytokines, and pro-apoptotic caspases, which cleave and activate pro-apoptotic substrates.

NECROSIS

An accidental cell death process that is characterized by an accompanying inflammatory response.

PURINERGIC RECEPTORS

A family of receptors that are stimulated by the purine nucleotides — ATP, ADP, AMP and UTP.

TYPE I CELLS

Cells that recruit caspase 8, which results in the subsequent cleavage of caspase 3.

TYPE II CELLS

Cells that activate caspase 3 through a mitochondria-dependent step.

BIOVARS

The phenotypical distinction of bacteria within the same species based on biological tests such as simple biochemical and/or enzymatic differences.

APOPTOSOME PATHWAY

A pathway of caspase activation that requires release of cytochrome c from the mitochondria.

PLAQUE ASSAY

An assay that allows visualization of the cytopathic effect of viruses or bacteria in a monolayer of host cells. The plaque centre lacks cells due to infection-induced lysis.

BH3-ONLY PROTEINS

Proteins that contain a BCL-2 homology (BH) 3 domain, but not the other BH domains usually found in BCL-2 family proteins. The BH3 domain is required to inhibit the activity of pro-survival proteins related to BCL-2.

CLOSTRIDIAL CYTOTOXIN HOMOLOGUES

Cytopathic toxins, found in many bacteria, which inactivate host-cell proteins that regulate actin polymerization, causing the cells to round up.

DEATH DOMAIN

A region of limited homology consisting of about 80 residues close to the intracellular carboxyl terminus of some cell-membrane receptors that is essential for the receptors to generate a signal leading to apoptosis.

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Byrne, G., Ojcius, D. Chlamydia and apoptosis: life and death decisions of an intracellular pathogen. Nat Rev Microbiol 2, 802–808 (2004). https://doi.org/10.1038/nrmicro1007

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