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  • Review Article
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Clostridium difficile colitis: pathogenesis and host defence

Key Points

  • Disease that is associated with infection by Clostridium difficile represents an urgent public health threat. The severity of C. difficile infection is determined by strain virulence, interactions with intestinal commensal microbial communities, and the host immune response to damage of the intestinal epithelium that is induced by C. difficile.

  • The ability to sporulate and germinate is essential to C. difficile virulence. Hundreds of genes that are involved in sporulation and germination have been identified as well as a bile acid receptor that induces germination.

  • C. difficile secretes toxin proteins that are internalized by host cells through receptor-mediated endocytosis and cause disruption to cytoskeletal architecture, which leads to cell death. Toxin-mediated cell death results in the loss of intestinal barrier integrity and the translocation of bacteria into underlying tissues.

  • The intestinal microbiota provides colonization resistance against C. difficile infection. Commensal bacteria that are capable of converting primary bile acids to secondary bile acids inhibit the growth of C. difficile by depriving C. difficile spores of an important germinant and by increasing the concentration of secondary bile acids in the intestinal lumen, which are toxic to the vegetative form of C. difficile.

  • Toxin-mediated damage to the epithelium activates the host inflammatory immune response. The role of the immune system is to limit epithelial damage and the dissemination of intestinal bacteria into the circulation. However, an overly robust inflammatory response can be damaging to the host and contribute to disease pathology.

Abstract

Clostridium difficile is a major cause of intestinal infection and diarrhoea in individuals following antibiotic treatment. Recent studies have begun to elucidate the mechanisms that induce spore formation and germination and have determined the roles of C. difficile toxins in disease pathogenesis. Exciting progress has also been made in defining the role of the microbiome, specific commensal bacterial species and host immunity in defence against infection with C. difficile. This Review will summarize the recent discoveries and developments in our understanding of C. difficile infection and pathogenesis.

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Figure 1: Sporulation and germination of C. difficile.
Figure 2: Mechanism of action of C. difficile toxins in epithelial cells.
Figure 3: Microbiota-mediated defences against C. difficile.
Figure 4: Innate immune-mediated defences against C. difficile.

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Acknowledgements

The Pamer Laboratory is supported by the US National Cancer Institute (NCI; core grant P30 CA008748) and the US National Institutes of Health (NIH; grants RO1 AI042135 and AI095706). M.C.A. is supported by the NIH (grant K99 AI125786). P.T.M. was supported by the NIH immunology training grant (T32CA009149).

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Glossary

Germination

The transformation of a dormant spore to an actively replicating bacterial cell.

Reverse genetics

Targeted alterations of the genome. In Clostridium difficile, tools include ClosTron and allelic replacement.

Forward genetics

Untargeted alterations of the genome that are achieved by chemical mutagens or transposable elements.

Sensor histidine kinases

Signal-sensing proteins that pass phosphate to response regulator transcription factors that alter gene expression in response to extracellular stimuli.

Sigma factor

The DNA-binding subunit of RNA polymerase, each sigma factor binds to a distinct consensus sequence.

Catabolite repression

The regulation of gene expression such that preferred carbon sources are metabolized first.

Sporangia

A cell of a spore-forming bacterium that has completed asymmetric division.

Vegetative growth

Normal exponential growth of bacteria in rich media. Clostridium difficile switches between vegetative growth and sporulation.

Prodomain

A peptide sequence at the amino terminus of a protein that is cleaved for the protein to be active and fully functional.

Riboswitch

A secondary structure of mRNA, typically in the 5′-untranslated region, that binds to small molecules and regulates transcription and/or translation in cis.

Type IV pili

Polymer filaments on the surface of Gram-positive and Gram-negative bacteria that facilitate motility or adhesion.

Bacteriocins

Ribosomally synthesized antimicrobial peptides that are produced by bacteria that can selectively act against specific bacterial species or exhibit broad-spectrum activity.

Inflammasome

A cytosolic multiprotein complex that detects pathogen-associated molecular patterns. The detection of these 'danger signals' activates transcription of pro-inflammatory cytokine genes.

Innate lymphoid cells

(ILCs). Haematopoietic-derived innate immune cells that are capable of producing effector cytokines tailored to coordinate the early host response against distinct classes of pathogen.

Complement pathway

A series of interactions between plasma-derived proteins that lead to the opsonization of a pathogen and activation of the inflammatory immune response.

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Abt, M., McKenney, P. & Pamer, E. Clostridium difficile colitis: pathogenesis and host defence. Nat Rev Microbiol 14, 609–620 (2016). https://doi.org/10.1038/nrmicro.2016.108

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