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Clostridioides difficile toxins: mechanisms of action and antitoxin therapeutics

Nature Reviews Microbiology volume 20, pages 285–298 (2022)Cite this article

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Abstract

Clostridioides difficile is a Gram-positive anaerobe that can cause a spectrum of disorders that range in severity from mild diarrhoea to fulminant colitis and/or death. The bacterium produces up to three toxins, which are considered the major virulence factors in C. difficile infection. These toxins promote inflammation, tissue damage and diarrhoea. In this Review, we highlight recent biochemical and structural advances in our understanding of the mechanisms that govern host–toxin interactions. Understanding how C. difficile toxins affect the host forms a foundation for developing novel strategies for treatment and prevention of C. difficile infection.

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Fig. 1: Structures of TcdA and TcdB.
Fig. 2: Intoxication mechanism of TcdA and TcdB.
Fig. 3: Progression of colon intoxication by the Clostridioides difficile toxins.
Fig. 4: Structure of the Clostridioides difficile transferase toxin.
Fig. 5: Intoxication mechanism of Clostridioides difficile transferase toxin.
Fig. 6: Biological therapeutic binding locations on TcdA and TcdB.

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Acknowledgements

The authors thank M. Sheedlo, H. Kroh, C. Peritore-Galve and J. Jensen for providing critical feedback. The authors are grateful to M. Sheedlo for guidance on making structural figures. Work in the Lacy laboratory is supported by NIH AI095755 and VA BX002943 grants with additional grant fellowship support to S.L.K. from NIH F32GM139303.

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  1. These authors contributed equally: Shannon L. Kordus, Audrey K. Thomas.

Authors and Affiliations

  1. Department of Pathology, Microbiology, and Immunology, Vanderbilt University Medical Center, Nashville, TN, USA

    Shannon L. Kordus, Audrey K. Thomas & D. Borden Lacy

  2. Center for Structural Biology, Vanderbilt University, Nashville, TN, USA

    Shannon L. Kordus, Audrey K. Thomas & D. Borden Lacy

  3. The Veterans Affairs Tennessee Valley Healthcare System, Nashville, TN, USA

    D. Borden Lacy

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Related links

DiffBase: https://diffbase.uwaterloo.ca/

Glossary

Pseudomembranous colitis

Inflammation of the colon characterized by raised yellow-white plaques of discarded epithelial and immune cells.

Toxic megacolon

A life-threatening condition characterized by non-obstructive, inflammatory dilation, expansion and distension of the colon.

Sequence types

Unique combinations of alleles grouped together on the basis of multilocus sequence typing.

Pyroptosis

A lytic and pro-inflammatory form of caspase 1-dependent programmed cell death.

Pyknosis

Irreversible chromatin condensation and nuclear dissolution during necrosis or apoptosis.

Two-component signal transduction system

A signal transduction pathway comprising a sensor that phosphorylates a response regulator in response to an environmental stimulus to elicit an effector function.

Designed ankyrin repeat proteins

(DARPins). Small protein scaffolds engineered to bind an antigen with high specificity and affinity, similar to monoclonal antibodies.

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Kordus, S.L., Thomas, A.K. & Lacy, D.B. Clostridioides difficile toxins: mechanisms of action and antitoxin therapeutics. Nat Rev Microbiol 20, 285–298 (2022). https://doi.org/10.1038/s41579-021-00660-2

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