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  • Review Article
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Chlamydia cell biology and pathogenesis

Nature Reviews Microbiology volume 14, pages 385–400 (2016)Cite this article

Subjects

Key Points

  • Chlamydia spp. are obligate intracellular pathogens that are important causes of human and animal diseases. Chlamydiae share a common developmental cycle in which they alternate between the extracellular, infectious elementary body and the intracellular, non-infectious reticulate body.

  • Chlamydiae use several redundant mechanisms to enter host cells and to establish their intracellular membrane bound niche — the inclusion.

  • Chlamydiae deliver effector proteins into the inclusion membrane and into host cells to promote replication and survival.

  • Chlamydiae encode a unique set of T3SS effectors, the inclusion membrane proteins (Incs), which are inserted into the inclusion membrane where they may function as structural determinants of the membrane or as scaffolds to interface with various cell pathways in the host.

  • Recent studies have solved the 'chlamydial anomaly' and reveal that Chlamydia spp. do synthesize peptidoglycan and use an atypical mechanism of cell division.

  • The recent major advances in chlamydial genetics open the door for the development of tools and avenues of research that were not previously accessible to this historically intractable pathogen.

Abstract

Chlamydia spp. are important causes of human disease for which no effective vaccine exists. These obligate intracellular pathogens replicate in a specialized membrane compartment and use a large arsenal of secreted effectors to survive in the hostile intracellular environment of the host. In this Review, we summarize the progress in decoding the interactions between Chlamydia spp. and their hosts that has been made possible by recent technological advances in chlamydial proteomics and genetics. The field is now poised to decipher the molecular mechanisms that underlie the intimate interactions between Chlamydia spp. and their hosts, which will open up many exciting avenues of research for these medically important pathogens.

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Figure 1: The life cycle of Chlamydia trachomatis.
Figure 2: Chlamydia–host interactions.
Figure 3: Modulation of host cell survival and death.
Figure 4: Modulation of the innate immune response.

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Acknowledgements

The authors apologize to those colleagues in the field whose work could not be included owing to space constraints. The authors gratefully acknowledge financial support from the US National Institutes of Health (R01 AI073770, AI105561 and AI122747) to J.E., and from the University of California, San Francisco (UCSF)-Gladstone Institute for Virology and Immunology, and the Center for AIDS Research to C.E.

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  1. Departments of Medicine, Microbiology and Immunology, University of California, San Francisco, 94143, California, USA

    Cherilyn Elwell, Kathleen Mirrashidi & Joanne Engel

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  1. Cherilyn Elwell
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Correspondence to Joanne Engel.

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Glossary

Biovars

Variants that differ physiologically and/or biochemically from other strains of a particular species.

Serovar

A subdivision of a species or subspecies that is distinguished by a characteristic set of antigens.

Type V secretion system

(T5SS). A system that exports autotransporters that are composed of a carboxy-terminal β-barrel translocator domain and an amino-terminal passenger domain that passes through the interior of the barrel to face the external environment.

Type II secretion system

(T2SS). A system that exports proteins across the bacterial inner membrane through the general secretory (Sec) pathway and across the outer membrane through secretin. In chlamydiae, T2SS effectors are secreted into the inclusion lumen, but can access the host cytosol through outer membrane vesicles.

Type III secretion system

(T3SS). A needle-like apparatus found in Gram-negative bacteria that delivers proteins, called effectors, across the inner and outer bacterial membranes and across eukaryotic membranes to the host membrane or the cytosol.

Homotypic fusion

The fusion between cells or vesicles of the same type. For cells that are infected with some Chlamydia spp., several inclusions undergo fusion with each other to form one, or a few, larger inclusions.

Sigma factors

Bacterial proteins that direct the binding of RNA polymerase to promoters, which enables the initiation of transcription.

Response regulators

Subunits of bacterial two-component signal transduction pathways that regulate output in response to an environmental stimulus.

Polymorphic membrane protein

(PMP). A member of a diverse group of surface-localized, immunodominant proteins that are secreted by the type V secretion system (T5SS) of Chlamydia spp.

ADP ribosylation factor 6

(ARF6). A member of the GTPase family of small GTPases that regulates vesicular transport, in which they function to recruit coat proteins that are necessary for the formation of vesicles.

Dynactin

A multisubunit complex found in eukaryotic cells that binds to the motor protein dynein and aids in the microtubule-based transport of vesicles.

SNARE proteins

(Soluble N-ethylmaleimide-sensitive factor (NSF) attachment protein receptor proteins). Soluble NSF attachment proteins are a large superfamily of proteins that mediate vesicle fusion by pairing with each other on adjacent membranes through SNARE domains.

RAB GTPases

Small GTPases that localize to the cytosolic face of specific intracellular membranes, where they regulate intracellular trafficking and membrane fusion. Different RABs are specific for distinct subcellular compartments.

Phosphoinositide lipid kinases

A family of enzymes that generates phosphorylated variants of phosphatidylinositols (secondary messengers), which are important for signalling and membrane remodelling. Organelles are, in part, identified by the specific lipid species that they contain.

Multivesicular bodies

(MVBs). A specialized set of late endosomes that contains internal vesicles formed by the inward budding of the outer endosomal membrane. MVBs are involved in protein sorting and are rich in lipids, including sphingolipids and cholesterol.

Dynamin

A large GTPase that is involved in the scission of newly formed vesicles from the cell surface, endosomes and the Golgi apparatus.

Ceramide endoplasmic reticulum transport protein

(CERT). A cytosolic protein that mediates the non-vesicular transport of ceramide from the endoplasmic reticulum to the Golgi apparatus where it is converted to sphingomyelin.

Type II fatty acid synthesis

A type of fatty acid synthesis in which the enzymes that catalyse each step in the synthesis pathway exist as distinct, individual proteins rather than as a multi-enzyme complex as in type I fatty acid synthesis.

Caspases

A family of cysteine proteases that has essential roles in apoptosis, necrosis and inflammation.

14-3-3 proteins

A family of conserved regulatory molecules that usually binds to a phosphoserine or phosphothreonine residue found in functionally diverse signalling proteins in eukaryotic cells.

Stimulator of interferon genes

(STING). A signalling molecule that recognizes cytosolic cyclic dinucleotides and activates the production of type I interferons.

Endoplasmic reticulum stress response

A stress pathway that is activated by perturbations in protein folding, lipid and steroid biosynthesis, and intracellular calcium stores.

Septins

A family of GTP-binding proteins that assembles into oligomeric complexes to form large filaments and rings that act as scaffolds and diffusion barriers

Chlamydia protease-like activity factor

(CPAF). A type II secreted broad-spectrum protease produced by Chlamydia spp. that may have a role in cleaving host proteins on release into the host cell cytosol late in infection or extracellularly following the lysis of the host cell.

BH3-only proteins

Members of the B cell lymphoma 2 (BCL-2) protein family, which are essential initiators of programmed cell death and are required for apoptosis that is induced by cytotoxic stimuli.

β-catenin–WNT pathway

A eukaryotic signal transduction pathway that signals through the binding of the WNT protein ligand to a frizzled family cell surface receptor, which results in changes to gene transcription, cell polarity or intracellular calcium levels.

Intrinsic and extrinsic apoptosis

A programmed form of cell death that involves the degradation of cellular constituents by caspases that are activated through either the intrinsic (mitochondria-mediated) or extrinsic (death receptor-mediated) apoptotic pathways.

p53

A eukaryotic tumour suppressor that maintains genome integrity by activating DNA repair, arresting the cell cycle or initiating apoptosis.

Cytokinesis

The physical process of cell division, which divides the cytoplasm of a parental cell into two daughter cells.

Toll-like receptors

(TLRs). Transmembrane proteins that have a key role in the innate immune system by recognizing pathogen-associated molecular patterns (PAMPs), which are structurally conserved molecules derived from microorganisms.

Type I interferons

(Type I IFNs). A subgroup of interferon proteins produced as part of the innate immune response against intracellular pathogens.

Nucleotide-binding oligomerization domain-containing 1

(NOD1). A cytosolic pattern-recognition receptor that recognizes bacterial peptidoglycan.

NLRP3–ASC inflammasome

A multiprotein complex, consisting of caspase1, NOD-, LRR- and PYD domain-containing protein 3 (NLRP3) and apoptosis-associated speck-like protein containing a CARD (ASC), that processes the pro-inflammatory cytokines interleukin-1β (IL-1β) and IL-18 into their mature forms.

Cell-autonomous immunity

The ability of a host cell to eliminate an invasive infectious agent, which relies on microbial proteins, specialized degradative compartments and programmed host cell death.

Nuclear factor-κB

(NF-κB) A protein complex that is translocated from the cytosol to the nucleus and regulates DNA transcription, cytokine production and cell survival in response to harmful cellular stimuli.

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Elwell, C., Mirrashidi, K. & Engel, J. Chlamydia cell biology and pathogenesis. Nat Rev Microbiol 14, 385–400 (2016). https://doi.org/10.1038/nrmicro.2016.30

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