scholarly journals Clostridioides difficile binary toxin binding component (CDTb) increases virulence in a hamster model

2021 ◽  
Author(s):  
Morgan Simpson ◽  
Terry Bilverstone ◽  
Jhansi L Leslie ◽  
Alexandra Donlan ◽  
Md Jashim Uddin ◽  
...  
Keyword(s):  
Binary Toxin ◽  
Gastrointestinal Infection ◽  
Hamster Model ◽  
Toxin Binding ◽  
Clostridioides Difficile ◽  
Hospital Acquired ◽  
Binding Component

Clostridioides difficile is the leading cause of hospital-acquired gastrointestinal infection, in part due to the existence of binary toxin (CDT)-expressing hypervirulent strains. We have previously shown that CDT interacts with the TLR2/6 heterodimer to induce inflammation, and in this study we further explore this interaction as well as the contribution of the separate components of CDT, CDTa and CDTb. We found that the binding component, CDTb, is capable of inducing inflammation. Additionally, complementation of a CDT-deficient C. difficile strain with CDTb alone restored virulence in a hamster model of C. difficile infection. Overall, this study demonstrates that the binding component of C. difficile binary toxin contributes to virulence during infection.

scholarly journals Phylogenomic analysis of Clostridioides difficile ribotype 106 strains reveals novel genetic islands and emergent phenotypes

2020 ◽  
Vol 10 (1) ◽  
Author(s):  
Bryan Angelo P. Roxas ◽  
Jennifer Lising Roxas ◽  
Rachel Claus-Walker ◽  
Anusha Harishankar ◽  
Asad Mansoor ◽  
...  
Keyword(s):  
Biofilm Formation ◽  
Diarrheal Disease ◽  
The United States ◽  
Genomic Islands ◽  
Rapid Expansion ◽  
Phylogenomic Analysis ◽  
Community Settings ◽  
Hamster Model ◽  
Clostridioides Difficile ◽  
Healthcare Associated

AbstractClostridioides difficile infection (CDI) is a major healthcare-associated diarrheal disease. Consistent with trends across the United States, C. difficile RT106 was the second-most prevalent molecular type in our surveillance in Arizona from 2015 to 2018. A representative RT106 strain displayed robust virulence and 100% lethality in the hamster model of acute CDI. We identified a unique 46 KB genomic island (GI1) in all RT106 strains sequenced to date, including those in public databases. GI1 was not found in its entirety in any other C. difficile clade, or indeed, in any other microbial genome; however, smaller segments were detected in Enterococcus faecium strains. Molecular clock analyses suggested that GI1 was horizontally acquired and sequentially assembled over time. GI1 encodes homologs of VanZ and a SrtB-anchored collagen-binding adhesin, and correspondingly, all tested RT106 strains had increased teicoplanin resistance, and a majority displayed collagen-dependent biofilm formation. Two additional genomic islands (GI2 and GI3) were also present in a subset of RT106 strains. All three islands are predicted to encode mobile genetic elements as well as virulence factors. Emergent phenotypes associated with these genetic islands may have contributed to the relatively rapid expansion of RT106 in US healthcare and community settings.

scholarly journals 2′FL and LNnT Exert Antipathogenic Effects against C. difficile ATCC 9689 In Vitro, Coinciding with Increased Levels of Bifidobacteriaceae and/or Secondary Bile Acids

Pathogens ◽  
2021 ◽  
Vol 10 (8) ◽  
pp. 927
Author(s):  
Louise Kristine Vigsnaes ◽  
Jonas Ghyselinck ◽  
Pieter Van den Van den Abbeele ◽  
Bruce McConnell ◽  
Frédéric Moens ◽  
...  
Keyword(s):  
Antimicrobial Effect ◽  
Secondary Bile Acid ◽  
Clostridioides Difficile ◽  
Life Threatening ◽  
Intermediate Time ◽  
Indigenous Microbiota ◽  
Hospital Acquired ◽  
Gut Microbial Community ◽  
Secondary Bile Acids

Clostridioides difficile (formerly Clostridium difficile) infection (CDI) is one of the most common hospital-acquired infections, which is often triggered by a dysbiosed indigenous gut microbiota (e.g., upon antibiotic therapy). Symptoms can be as severe as life-threatening colitis. The current study assessed the antipathogenic potential of human milk oligosaccharides (HMOs), i.e., 2′-O-fucosyllactose (2′FL), lacto-N-neotetraose (LNnT), and a combination thereof (MIX), against C. difficile ATCC 9689 using in vitro gut models that allowed the evaluation of both direct and, upon microbiota modulation, indirect effects. During a first 48 h fecal batch study, dysbiosis and CDI were induced by dilution of the fecal inoculum. For each of the three donors tested, C. difficile levels strongly decreased (with >4 log CFU/mL) upon treatment with 2′FL, LNnT and MIX versus untreated blanks, coinciding with increased acetate/Bifidobacteriaceae levels. Interindividual differences among donors at an intermediate time point suggested that the antimicrobial effect was microbiota-mediated rather than being a direct effect of the HMOs. During a subsequent 11 week study with the PathogutTM model (specific application of the Simulator of the Human Intestinal Microbial Ecosystem (SHIME®)), dysbiosis and CDI were induced by clindamycin (CLI) treatment. Vancomycin (VNC) treatment cured CDI, but the further dysbiosis of the indigenous microbiota likely contributed to CDI recurrence. Upon co-supplementation with VNC, both 2′FL and MIX boosted microbial activity (acetate and to lesser extent propionate/butyrate). Moreover, 2′FL avoided CDI recurrence, potentially because of increased secondary bile acid production. Overall, while not elucidating the exact antipathogenic mechanisms-of-action, the current study highlights the potential of HMOs to combat CDI recurrence, help the gut microbial community recover after antibiotic treatment, and hence counteract the adverse effects of antibiotic therapies.

scholarly journals 10 Years of Pulsed-Xenon Ultraviolet Disinfection

2020 ◽  
Vol 41 (S1) ◽  
pp. s438-s438
Author(s):  
Mark Stibich ◽  
Sarah Simmons ◽  
Deborah Passey
Keyword(s):  
Relative Risk ◽  
Meta Analysis ◽  
Outcome Studies ◽  
Uv Disinfection ◽  
Clostridioides Difficile ◽  
Environmental Effectiveness ◽  
Meta Analyses ◽  
Hospital Acquired ◽  
And Control ◽  
Effectiveness Studies

Background: Ultraviolet light (UV) disinfection using low-pressure mercury lamps has been around since the 1940s. The advent of pulsed-xenon UV for hospital use in 2010 has provided a nontoxic and novel technology for hospital disinfection with the first data presented at the 2010 SHEA Decennial. The purpose of this systematic review and meta-analysis is to examine the current body of evidence for pulsed xenon UV disinfection. Methods: The literature search criteria included the following: research conducted in domestic and international settings using pulsed-xenon for surface disinfection, published between 2000 and 2019, and reporting on environmental effectiveness or hospital-acquired reductions (HAIs). We searched PubMed, Google Scholar, and Web of Science. The meta-analysis included 24 studies: 12 HAI outcome studies and 12 environmental effectiveness studies. Meta-analyses were conducted by calculating the percentage reductions for environmental effectiveness, and for the HAI outcome studies, we used a random-effects model to pool the relative risk of HAI. The outcome studies used 272 and 299 months of data for the experimental and control groups, respectively. Results: There was an overall benefit of using pulsed-xenon UV. The overall relative risk of infection decreased compared to the control arm (RR, 0.64; 95% CI, 0.54–0.76). The percentage reductions in environmental studies were as follows: Clostridioides difficile (94.8%), methicillin-resistant Staphylococcus aureus (91.5%), vancomycin-resistant Enterococcus (99.2%), and aerobic bacteria (94.2%). Conclusions: Overall, pulsed-xenon UV was effective for reducing environmental contamination and had the ability to significantly reduce HAIs.Funding: Xenex, Inc., funded this study.Disclosures: Mark Stibich receives a salary from Xenex and is a shareholder of Xenex. Deborah Passey receives a salary from Xenex Disinfection Services.

scholarly journals The Importance of Therapeutically Targeting the Binary Toxin from Clostridioides difficile

2021 ◽  
Vol 22 (6) ◽  
pp. 2926
Author(s):  
Dinendra L. Abeyawardhane ◽  
Raquel Godoy-Ruiz ◽  
Kaylin A. Adipietro ◽  
Kristen M. Varney ◽  
Richard R. Rustandi ◽  
...  
Keyword(s):  
Host Cell ◽  
The Elderly ◽  
Cell Receptor ◽  
Host Cells ◽  
Binary Toxin ◽  
Clostridioides Difficile ◽  
Host Cell Receptor ◽  
Oligomeric Assembly ◽  
Nosocomial Disease ◽  
Binary Toxins

Novel therapeutics are needed to treat pathologies associated with the Clostridioides difficile binary toxin (CDT), particularly when C. difficile infection (CDI) occurs in the elderly or in hospitalized patients having illnesses, in addition to CDI, such as cancer. While therapies are available to block toxicities associated with the large clostridial toxins (TcdA and TcdB) in this nosocomial disease, nothing is available yet to treat toxicities arising from strains of CDI having the binary toxin. Like other binary toxins, the active CDTa catalytic subunit of CDT is delivered into host cells together with an oligomeric assembly of CDTb subunits via host cell receptor-mediated endocytosis. Once CDT arrives in the host cell’s cytoplasm, CDTa catalyzes the ADP-ribosylation of G-actin leading to degradation of the cytoskeleton and rapid cell death. Although a detailed molecular mechanism for CDT entry and host cell toxicity is not yet fully established, structural and functional resemblances to other binary toxins are described. Additionally, unique conformational assemblies of individual CDT components are highlighted herein to refine our mechanistic understanding of this deadly toxin as is needed to develop effective new therapeutic strategies for treating some of the most hypervirulent and lethal strains of CDT-containing strains of CDI.

scholarly journals Colonisation Factor CD0873, an Attractive Oral Vaccine Candidate against Clostridioides difficile

2021 ◽  
Vol 9 (2) ◽  
pp. 306
Author(s):  
Cansu Karyal ◽  
Jaime Hughes ◽  
Michelle L. Kelly ◽  
Jeni C. Luckett ◽  
Philip V. Kaye ◽  
...  
Keyword(s):  
Pseudomembranous Colitis ◽  
Vaccine Candidate ◽  
Oral Vaccine ◽  
Immunoglobulin A ◽  
Oral Route ◽  
Hamster Model ◽  
Clostridioides Difficile ◽  
Mucosal Antibody ◽  
Gut Pathogens ◽  
Secretory Immunoglobulin

Clostridioides difficile is the main cause of health-care-associated infectious diarrhoea. Toxins, TcdA and TcdB, secreted by this bacterium damage colonic epithelial cells and in severe cases this culminates in pseudomembranous colitis, toxic megacolon and death. Vaccines in human trials have focused exclusively on the parenteral administration of toxin-based formulations. These vaccines promote toxin-neutralising serum antibodies but fail to confer protection from infection in the gut. An effective route to immunise against gut pathogens and stimulate a protective mucosal antibody response (secretory immunoglobulin A, IgA) at the infection site is the oral route. Additionally, oral immunisation generates systemic antibodies (IgG). Using this route, two different antigens were tested in the hamster model: The colonisation factor CD0873 and a TcdB fragment. Animals immunised with CD0873 generated a significantly higher titre of sIgA in intestinal fluid and IgG in serum compared to naive animals, which significantly inhibited the adherence of C. difficile to Caco-2 cells. Following challenge with a hypervirulent isolate, the CD0873-immunised group showed a mean increase of 80% in time to experimental endpoint compared to naïve animals. Survival and body condition correlated with bacterial clearance and reduced pathology in the cecum. Our findings advocate CD0873 as a promising oral vaccine candidate against C. difficile.

scholarly journals Binding Component of Clostridium perfringens Iota-Toxin Induces Endocytosis in Vero Cells

2002 ◽  
Vol 70 (4) ◽  
pp. 1909-1914 ◽  
Author(s):  
Masahiro Nagahama ◽  
Koichi Nagayasu ◽  
Keiko Kobayashi ◽  
Jun Sakurai
Keyword(s):  
Clostridium Perfringens ◽  
Vero Cells ◽  
Binary Toxin ◽  
Wild Type ◽  
Oligomer Formation ◽  
Clostridium Perfringens Iota Toxin ◽  
Binding Component ◽  
Pronase Treatment

ABSTRACT Clostridium perfringens iota-toxin is a binary toxin consisting of two individual proteins, the binding component (Ib) and the enzyme component (Ia). Wild-type Ib bound to Vero cells at 4 and 37°C and formed oligomers at 37°C but not at 4°C. The Ib-induced K+ release from the cells was dependent on the oligomer formation of Ib in the cells, but the oligomer formation did not induce rounding activity or cytotoxicity. After incubation of the cells with recombinant Ib (rIb) at 37°C, the Ib oligomer in the cell became resistant to pronase treatment with time, but the Ib monomer was sensitive to the treatment. Furthermore, treatment of Vero cells with rIb in the presence of bafilomycin, methylamine, or ethylamine resulted in accumulation of the oligomer in the cells but had no effect on K+ release. Moreover, incubation with Ib plus Ia in the presence of these agents caused no rounding in the cells. These observations suggest that Ib binds to Vero cells, itself oligomerizing to form ion-permeable channels and that the formation of oligomer then induces endocytosis.

scholarly journals Impact of a division-wide bundle on hospital-acquired Clostridioides difficile cases, antibiotic days of therapy, testing appropriateness, and associated financial costs

2021 ◽  
Vol 11 (1) ◽  
pp. 27
Author(s):  
Mayar Al Mohajer ◽  
ElizabethWenqian Wang ◽  
Ashlee Weekley ◽  
Jennifer McCarty ◽  
Hoonmo Koo ◽  
...  
Keyword(s):  
Clostridioides Difficile ◽  
Financial Costs ◽  
Days Of Therapy ◽  
Hospital Acquired

scholarly journals Novel Drivers of Virulence in Clostridioides difficile Identified via Context-Specific Metabolic Network Analysis

mSystems ◽  
2021 ◽  
Author(s):  
Matthew L. Jenior ◽  
Jhansi L. Leslie ◽  
Deborah A. Powers ◽  
Elizabeth M. Garrett ◽  
Kimberly A. Walker ◽  
...  
Keyword(s):  
Network Analysis ◽  
Metabolic Network ◽  
Virulence Factors ◽  
Metabolic Pathways ◽  
Content Type ◽  
Hospital Acquired Infections ◽  
Metabolic Network Analysis ◽  
Clostridioides Difficile ◽  
Context Specific ◽  
Hospital Acquired

Clostridioides difficile has become the leading single cause of hospital-acquired infections. Numerous studies have demonstrated the importance of specific metabolic pathways in aspects of C. difficile pathophysiology, from initial colonization to regulation of virulence factors.

scholarly journals The interplay of SARS-CoV-2 and Clostridioides difficile infection

2021 ◽  
Vol 16 (6) ◽  
pp. 439-443
Author(s):  
Sahil Khanna ◽  
Colleen S Kraft
Keyword(s):  
High Risk ◽  
Infection Control ◽  
Gastrointestinal Symptoms ◽  
Control Measures ◽  
Antibiotic Exposure ◽  
Hospital Acquired Infections ◽  
Infection Control Measures ◽  
Clostridioides Difficile ◽  
Clostridioides Difficile Infection ◽  
Hospital Acquired

The COVID-19 pandemic has changed the way we practice medicine and lead our lives. In addition to pulmonary symptoms; COVID-19 as a syndrome has multisystemic involvement including frequent gastrointestinal symptoms such as diarrhea. Due to microbiome alterations with COVID-19 and frequent antibiotic exposure, COVID-19 can be complicated by Clostridioides difficile infection. Co-infection with these two can be associated with a high risk of complications. Infection control measures in hospitals is enhanced due to the COVID-19 pandemic which in turn appears to reduce the incidence of hospital-acquired infections such as C. difficile infection. Another implication of COVID-19 and its potential transmissibility by stool is microbiome-based therapies. Potential stool donors should be screened COVID-19 symptoms and be tested for COVID-19.

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