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      Clostridium difficile binary toxin CDT : Mechanism, epidemiology, and potential clinical importance

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          Abstract

          Binary toxin (CDT) is frequently observed in Clostridium difficile strains associated with increased severity of C. difficile infection (CDI). CDT belongs to the family of binary ADP-ribosylating toxins consisting of two separate toxin components: CDTa, the enzymatic ADP-ribosyltransferase which modifies actin, and CDTb which binds to host cells and translocates CDTa into the cytosol. CDTb is activated by serine proteases and binds to lipolysis stimulated lipoprotein receptor. ADP-ribosylation induces depolymerization of the actin cytoskeleton. Toxin-induced actin depolymerization also produces microtubule-based membrane protrusions which form a network on epithelial cells and increase bacterial adherence. Multiple clinical studies indicate an association between binary toxin genes in C. difficile and increased 30-d CDI mortality independent of PCR ribotype. Further studies including measures of binary toxin in stool, analyses of CDI mortality caused by CDT-producing strains, and examination of the relationship of CDT expression to TcdA and TcdB toxin variants and PCR ribotypes are needed.

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          Actin, a central player in cell shape and movement.

          Thomas Pollard, John Cooper (2009)
          The protein actin forms filaments that provide cells with mechanical support and driving forces for movement. Actin contributes to biological processes such as sensing environmental forces, internalizing membrane vesicles, moving over surfaces, and dividing the cell in two. These cellular activities are complex; they depend on interactions of actin monomers and filaments with numerous other proteins. Here, we present a summary of the key questions in the field and suggest how those questions might be answered. Understanding actin-based biological phenomena will depend on identifying the participating molecules and defining their molecular mechanisms. Comparisons of quantitative measurements of reactions in live cells with computer simulations of mathematical models will also help generate meaningful insights.
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            Emergence of Clostridium difficile infection due to a new hypervirulent strain, polymerase chain reaction ribotype 078.

            Abraham Goorhuis, Dennis Bakker, Jeroen Corver … (2008)
            Since 2005, an increase in the prevalence of Clostridium difficile infection (CDI) due to polymerase chain reaction ribotype 078 has been noticed in The Netherlands. This strain has also been identified as the predominant strain in pigs and calves. CDI caused by type 078 was studied in relation to CDI caused by the hypervirulent type 027 and by types other than 027 and 078. Human and porcine isolates were further investigated and characterized by multilocus variable number tandem repeat analysis. From February 2005 through February 2008, the incidence of type 078 among isolates obtained from 1687 patients increased from 3% to 13%. Compared with patients infected with type 027, patients infected with type 078 were younger (67.4 vs. 73.5 years; P < .01) and more frequently had community-associated disease (17.5% vs. 6.7%; odds ratio, 2.98; 95% confidence interval, 2.11-8.02); rates of severe diarrhea (38.9% vs. 40.0%) and attributable mortality (3.8% vs. 4.0%) were similar in both groups. Compared with patients infected with other types, patients infected with type 078 more frequently received fluoroquinolone therapy (29.4% vs. 19.8%; odds ratio, 2.17; 95% confidence interval, 1.06-4.44). Type 078 isolates contained genes for toxin A, toxin B, binary toxin, and a 39-base pair deletion in toxin regulator gene (tcdC), as well as a point mutation at position 184, resulting in a stop codon. Multilocus variable number tandem repeat analysis of 54 human and 11 porcine isolates revealed 4 clonal complexes containing both porcine and human isolates. CDI due to type 078 and CDI due to type 027 present with similar severity, but CDI due to type 078 affects a younger population and is more frequently community associated. C. difficile type 078 isolates from humans and pigs are highly genetically related.
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              Treatment with monoclonal antibodies against Clostridium difficile toxins.

              Israel Lowy, Deborah Molrine, Brett Leav … (2010)
              New therapies are needed to manage the increasing incidence, severity, and high rate of recurrence of Clostridium difficile infection. We performed a randomized, double-blind, placebo-controlled study of two neutralizing, fully human monoclonal antibodies against C. difficile toxins A (CDA1) and B (CDB1). The antibodies were administered together as a single infusion, each at a dose of 10 mg per kilogram of body weight, in patients with symptomatic C. difficile infection who were receiving either metronidazole or vancomycin. The primary outcome was laboratory-documented recurrence of infection during the 84 days after the administration of monoclonal antibodies or placebo. Among the 200 patients who were enrolled (101 in the antibody group and 99 in the placebo group), the rate of recurrence of C. difficile infection was lower among patients treated with monoclonal antibodies (7% vs. 25%; 95% confidence interval, 7 to 29; P<0.001). The recurrence rates among patients with the epidemic BI/NAP1/027 strain were 8% for the antibody group and 32% for the placebo group (P=0.06); among patients with more than one previous episode of C. difficile infection, recurrence rates were 7% and 38%, respectively (P=0.006). The mean duration of the initial hospitalization for inpatients did not differ significantly between the antibody and placebo groups (9.5 and 9.4 days, respectively). At least one serious adverse event was reported by 18 patients in the antibody group and by 28 patients in the placebo group (P=0.09). The addition of monoclonal antibodies against C. difficile toxins to antibiotic agents significantly reduced the recurrence of C. difficile infection. (ClinicalTrials.gov number, NCT00350298.) 2010 Massachusetts Medical Society
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                Author and article information

                Journal
                Journal ID (nlm-ta): Gut Microbes
                Journal ID (iso-abbrev): Gut Microbes
                Journal ID (publisher-id): GMIC
                Title: Gut Microbes
                Publisher: Landes Bioscience
                ISSN (Print): 1949-0976
                ISSN (Electronic): 1949-0984
                Publication date (Print): 01 January 2014
                Publication date (Electronic): 31 October 2013
                Volume: 5
                Issue: 1
                Pages: 15-27
                Affiliations
                [1 ]Loyola University Chicago Stritch School of Medicine; Hines Veterans Affairs Hospital; Hines, IL USA
                [2 ]Institute of Public Health Maribor; University of Maribor, Medical Faculty, and Centre of Excellence for Integrated Approaches in Chemistry and Biology of Proteins; Ljubljana, Slovenia
                [3 ]Institute of Experimental and Clinical Pharmacology and Toxicology; Albert-Ludwigs-University Freiburg; Freiburg, Germany
                Author notes
                [* ]Correspondence to: Dale N Gerding, Email: Dale.Gerding2@ 123456med.va.gov
                Article
                Publisher ID: 2013GUTMICROBES0032R1 Publisher Item ID: 26854
                DOI: 10.4161/gmic.26854
                PMC ID: 4049931
                PubMed ID: 24253566
                SO-VID: 92670ae2-a271-4f7c-b280-c413656755ff
                Copyright © Copyright © 2014 Landes Bioscience
                License:

                This is an open-access article licensed under a Creative Commons Attribution-NonCommercial 3.0 Unported License. The article may be redistributed, reproduced, and reused for non-commercial purposes, provided the original source is properly cited.

                History
                Date received : 19 March 2013
                Date revision received : 23 September 2013
                Date accepted : 17 October 2013
                Categories
                Subject: Review

                ScienceOpen disciplines: Microbiology & Virology
                Keywords: clostridium difficile infection,binary toxin,cdt,mechanism,mortality,disease severity,toxinotyping,pcr ribotyping
                Data availability:
                ScienceOpen disciplines: Microbiology & Virology
                Keywords: clostridium difficile infection, binary toxin, cdt, mechanism, mortality, disease severity, toxinotyping, pcr ribotyping

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