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Enterotoxic Clostridia: Infections

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  • Authors: S. Mileto1, A. Das2, D. Lyras3
  • Editors: Vincent A. Fischetti4, Richard P. Novick5, Joseph J. Ferretti6, Daniel A. Portnoy7, Julian I. Rood8
  • VIEW AFFILIATIONS HIDE AFFILIATIONS
    Affiliations: 1: Infection and Immunity Program, Monash Biomedicine Discovery Institute and Department of Microbiology, Monash University, Clayton, Victoria, Australia, 3800; 2: Infection and Immunity Program, Monash Biomedicine Discovery Institute and Department of Microbiology, Monash University, Clayton, Victoria, Australia, 3800; 3: Infection and Immunity Program, Monash Biomedicine Discovery Institute and Department of Microbiology, Monash University, Clayton, Victoria, Australia, 3800; 4: The Rockefeller University, New York, NY; 5: Skirbaell Institute for Molecular Medicine, NYU Medical Center, New York, NY; 6: Department of Microbiology & Immunology, University of Oklahoma Health Science Center, Oklahoma City, OK; 7: Department of Molecular and Cellular Microbiology, University of California, Berkeley, Berkeley, CA; 8: Australian Bacterial Pathogen Program, Department of Microbiology, Monash University, Melbourne, Australia
  • Source: microbiolspec May 2019 vol. 7 no. 3 doi:10.1128/microbiolspec.GPP3-0015-2018
  • Received 12 April 2018 Accepted 17 April 2018 Published 24 May 2019
  • Dena Lyras, [email protected]
image of Enterotoxic Clostridia: <span class="jp-italic">Clostridioides difficile</span> Infections
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  • Abstract:

    is a Gram-positive, anaerobic, spore forming pathogen of both humans and animals and is the most common identifiable infectious agent of nosocomial antibiotic-associated diarrhea. Infection can occur following the ingestion and germination of spores, often concurrently with a disruption to the gastrointestinal microbiota, with the resulting disease presenting as a spectrum, ranging from mild and self-limiting diarrhea to severe diarrhea that may progress to life-threating syndromes that include toxic megacolon and pseudomembranous colitis. Disease is induced through the activity of the toxins TcdA and TcdB, both of which disrupt the Rho family of GTPases in host cells, causing cell rounding and death and leading to fluid loss and diarrhea. These toxins, despite their functional and structural similarity, do not contribute to disease equally. infection (CDI) is made more complex by a high level of strain diversity and the emergence of epidemic strains, including ribotype 027-strains which induce more severe disease in patients. With the changing epidemiology of CDI, our understanding of disease, diagnosis, and pathogenesis continues to evolve. This article provides an overview of the current diagnostic tests available for CDI, strain typing, the major toxins produces and their mode of action, the host immune response to each toxin and during infection, animal models of disease, and the current treatment and prevention strategies for CDI.

  • Citation: Mileto S, Das A, Lyras D. 2019. Enterotoxic Clostridia: Infections. Microbiol Spectrum 7(3):GPP3-0015-2018. doi:10.1128/microbiolspec.GPP3-0015-2018.

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/content/journal/microbiolspec/10.1128/microbiolspec.GPP3-0015-2018
2019-05-24
2019-08-25

Abstract:

is a Gram-positive, anaerobic, spore forming pathogen of both humans and animals and is the most common identifiable infectious agent of nosocomial antibiotic-associated diarrhea. Infection can occur following the ingestion and germination of spores, often concurrently with a disruption to the gastrointestinal microbiota, with the resulting disease presenting as a spectrum, ranging from mild and self-limiting diarrhea to severe diarrhea that may progress to life-threating syndromes that include toxic megacolon and pseudomembranous colitis. Disease is induced through the activity of the toxins TcdA and TcdB, both of which disrupt the Rho family of GTPases in host cells, causing cell rounding and death and leading to fluid loss and diarrhea. These toxins, despite their functional and structural similarity, do not contribute to disease equally. infection (CDI) is made more complex by a high level of strain diversity and the emergence of epidemic strains, including ribotype 027-strains which induce more severe disease in patients. With the changing epidemiology of CDI, our understanding of disease, diagnosis, and pathogenesis continues to evolve. This article provides an overview of the current diagnostic tests available for CDI, strain typing, the major toxins produces and their mode of action, the host immune response to each toxin and during infection, animal models of disease, and the current treatment and prevention strategies for CDI.

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Image of FIGURE 1
FIGURE 1

Schematic representation of the pathogenicity locus (PaLoc) and transferase locus (CDTLoc) and flanking genes. The PaLoc chromosomal region is responsible for both the production and regulation of the major toxins TcdA and TcdB (encoded by and ), which are critical for pathogenesis, virulence, and the disease symptoms of CDI. PaLoc also encodes genes involved in the positive () and negative () regulation of toxin production, as well as a gene () encoding a holin-like protein, TcdE, which may be involved in the release of toxins from the cell. Nontoxigenic strains lack this region and are consequently avirulent. The CDTLoc chromosomal region is responsible for both the production and regulation of CDT/binary toxin (encoded by and ). CDTLoc also encodes a gene involved in the positive regulation of CDT (). Modified from ( 8 ).

Source: microbiolspec May 2019 vol. 7 no. 3 doi:10.1128/microbiolspec.GPP3-0015-2018
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Image of FIGURE 2
FIGURE 2

Schematic representation of TcdA and TcdB. Comparison of TcdA and TcdB functional domains. Comparison of the four functional domains of the toxins, including the glucosyltransferase domain (GTD) (red), auto-protease domain (APD) (blue), delivery domain (yellow), and combined repetitive oligo-peptides (CROPS) domain (gray). The crystal structure of the TcdA GTD (red), APD (blue), and delivery domains (yellow) in the absence of the binding domain. Three-dimensional structure of TcdA, superimposed with the crystal structure of TcdA. Reprinted from ( 254 ).

Source: microbiolspec May 2019 vol. 7 no. 3 doi:10.1128/microbiolspec.GPP3-0015-2018
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FIGURE 3

Binding and entry of toxins into colonic epithelial cells. TcdA and TcdB bind to the cell surface via interaction of the binding region and one or more cell surface receptors, including the α-Gal-(1,3)-β-Gal-(1,4)-β-GlcNAcO(CH)COCH carbohydrate moiety and glycoprotein 96 (gp96) or surface receptors including frizzled (FZD), chondroitin sulfate proteoglycan 4 (CSPG4), and poliovirus-like receptor 3 (PVLR3) respectively, resulting in receptor-mediated endocytosis. Binding can occur via CROPS (green)-dependent and -independent mechanisms. Once internalized, the endosome acidifies, resulting in a conformational change and membrane insertion of the delivery domain and translocation of the auto-protease domain (APD; gray) and glucosyltransferase (GTD; red) into the cytosol. The APD then interacts with host inositol hexakisphosphate (InsP6; blue), cleaving the GTD, which can interact with the Rho family of GTPases. Reprinted from ( 254 ).

Source: microbiolspec May 2019 vol. 7 no. 3 doi:10.1128/microbiolspec.GPP3-0015-2018
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FIGURE 4

Comparison of the TcdA and TcdB combined repetitive oligopeptides (CROPS) domains. Three-dimensional models of the TcdA and TcdB CROPS domains based on the crystal structure of a 127-amino acid fragment from the C-terminal region of TcdA characterized in reference 177 . Long repeats are in green; short repeats are in blue. N, N terminus; C, C terminus. Modified from ( 157 ).

Source: microbiolspec May 2019 vol. 7 no. 3 doi:10.1128/microbiolspec.GPP3-0015-2018
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