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Molecular pathogenesis of the obligate intracellular bacterium Coxiella burnetii

Key Points

  • Coxiella burnetii is a Gram-negative obligate intracellular bacterial pathogen that is the aetiological agent of Q fever, which manifests as both acute and chronic infections. The infection is a zoonosis that is most often transmitted by aerosolized dry, contaminated soil or animal products.

  • Genetic differences between C. burnetii isolates from acute and chronic infections have led to the hypothesis that pathotype-specific virulence exists.

  • After inhalation by a host, C. burnetii invades and replicates within alveolar macrophages without alerting the innate immune system and has therefore been described as a stealth pathogen. Inside macrophages, the bacterium replicates within a compartment that is very similar to a phagolysosome, termed the Coxiella-containing vacuole (CCV).

  • C. burnetii has a type IV secretion system that resembles the Dot/Icm (defect in organelle trafficking/intracellular multiplication) system of Legionella pneumophila and is necessary for pathogenesis. C. burnetii encodes homologues for 24 of the 27 L. pneumophila Dot/Icm proteins, and four C. burnetii Dot/Icm genes can actually complement homologous mutations in the L. pneumophila system, lending strength to the conjecture that these systems are structurally and functionally similar.

  • Establishment and maintenance of the CCV is dependent on protein production by C. burnetii. Although the identity of the virulence factors involved are unknown, new evidence suggests that most are effectors secreted by the type IV secretion system.

  • The recent development of axenic media to grow C. burnetii has enabled the development of genetic tools to identify virulence factors. These developments have started a new era of research for C. burnetii, and Koch's postulates can now be tested for the first time.

Abstract

The agent of Q fever, Coxiella burnetii, is an obligate intracellular bacterium that causes acute and chronic infections. The study of C. burnetii pathogenesis has benefited from two recent fundamental advances: improved genetic tools and the ability to grow the bacterium in extracellular media. In this Review, we describe how these recent advances have improved our understanding of C. burnetii invasion and host cell modulation, including the formation of replication-permissive Coxiella-containing vacuoles. Furthermore, we describe the Dot/Icm (defect in organelle trafficking/intracellular multiplication) system, which is used by C. burnetii to secrete a range of effector proteins into the host cell, and we discuss the role of these effectors in remodelling the host cell.

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Figure 1: The intracellular trafficking pathway of Coxiella burnetii.
Figure 2: The type IVB secretion systems of Coxiella burnetii and Legionella pneumophila.
Figure 3: Roles of type IV secretion system effectors during Coxiella burnetii intracellular infection.

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Acknowledgements

This work was supported by US National Institutes of Health grants AI037744, U54 AI057156, AI078213, AI088430, AI090142, and AI092153 (to J.E.S.). The authors thank L. R. Hendrix, K. Russell-Lodrigue and C. Farris for critical review and helpful discussions.

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Glossary

Axenic culture media

Media used for the growth of intracellular bacteria in the absence of host cells.

Category B select agent

An infectious disease agent of the second highest priority, as defined by the US CDC guidelines for potential misuse. These agents are usually readily transmitted by aerosol, are stable in the environment and cause moderate morbidity and low mortality.

BL3 containment

A level of biocontainment that includes a separation from general traffic areas by double doors, airlocks and negative air flow. Access is limited to trained personnel and requires users to wear personal protective equipment. All research activities with potential exposure of the agent to the atmosphere are conducted within biosafety cabinets.

Integrin

A highly conserved family of heterodimeric surface glycoproteins involved in binding to extracellular matrix components such as fibronectin and vitronectin through arginine-glycine-aspartic acid (RGD) domains.

BL2 containment

A level of biocontainment that involves the use of standard laboratory space in which work using an infectious agent is carried out within a biosafety cabinet.

SRC tyrosine kinases

A family of kinases that was originally identified through homology to Rous sarcoma virus oncogene v-src and is involved in signal transduction from cellular receptors.

Cachexia

Loss of weight, fatigue and weakness that are associated with severe inflammatory disease and cannot be reversed by nutritional supplementation.

Himar1-based transposon system

A eukaryotic horn fly element that is extensively used to create mutations in bacteria and relies on only an AT dinucleotide for insertion.

C. burnetii str. Nine Mile I

The original Coxiella burnetii strain isolated from ticks in 1935. This strain was later serially passaged in embryonated hen eggs and guinea pigs to obtain the avirulent isolate C. burnetii str. Nine Mile II.

Two-component regulatory system

A bacterial signal transduction system involving a sensor kinase that responds to an environmental stimulus by phosphorylating a response regulator, which controls the transcription of downstream genes.

Insertion sequences

Mobile genetic elements consisting of short inverted repeats flanking one or more ORFs.

Ankyrin repeats

Eukaryotic protein domains consisting of repeating segments of 33 amino acids that form a helix–turn–helix motif and mediate protein–protein interactions. These domains are some of the most commonly found domains in eukaryotic proteins.

Coiled-coil domains

Structural motifs that are found in proteins and consist of 2–5 α-helices wrapped around each other in a left-handed manner to form a superhelix.

Tetratricopeptide repeats

Structural motifs that mediate protein–protein interactions and are composed of a degenerate 34 amino acid sequence that is often arranged in a tandem array.

F-box domains

Structural motifs composed of approximately 50 amino acids and that contain tryptophan-aspartic acid repeats. These domains function as protein–protein interaction domains. F-box proteins were first characterized as components of ubiquitin ligase complexes.

Fic domains

(Filamentation induced by cyclic AMP domains). Protein domains that mediate ampylation of proteins and regulate protein function.

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van Schaik, E., Chen, C., Mertens, K. et al. Molecular pathogenesis of the obligate intracellular bacterium Coxiella burnetii. Nat Rev Microbiol 11, 561–573 (2013). https://doi.org/10.1038/nrmicro3049

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