The binary toxin CDT enhances Clostridium difficile virulence by suppressing protective colonic eosinophilia

Cowardin, Carrie A.; Buonomo, Erica L.; Saleh, Mahmoud; Wilson, Madeline G.; Burgess, Stacey L.; Kuehne, Sarah A.; Schwan, Carsten; Eichhoff, Anna Marei; Koch-Nolte, Friedrich; Lyras, Dena; Aktories, Klaus; Minton, Nigel P.; Petri, William A.

doi:10.1038/nmicrobiol.2016.108

Cited by 153 publications

(169 citation statements)

References 52 publications

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“…Previous data have found that the patients infected with C. difficile producing CDT had higher fatality rate (approximately 60%) than those infected with CDT-deficient strains [13]. A more recent study found that the binary toxin enhanced two PCR-ribotype 027 strains (R20291 and M7404) in mice by suppressing protective colonic eosinophilia [50]. Sequence comparisons demonstrated that the CdtLoc harbored in the ST201 strains was highly homologous to that of strain R20291, and the three genes cdtA, ctdB and ctdR carried by the ST201 CdtLoc were intact and also highly homologous to their corresponding genes harbored by R20291, respectively.…”

Section: Discussionmentioning

confidence: 99%

Genome Characterization of a Novel Binary Toxin-Positive Strain of <em>Clostridium difficile</em> and Comparison with the Epidemic 027 and 078 Strains

Peng¹,

Han²,

Meng³

et al. 2017

Preprint

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Abstract:A novel binary toxin-positive non-027, non-078 Clostridium difficile strain designated LC693 whose sequence type was ST201 was isolated from the fecal sample of a patient with severe diarrhea in China. To understand the pathogenesis basis of C. difficile ST201, this recently recovered isolate LC693 was then chosen for whole genome sequencing. The project finally generated an estimated genome size of approximately 4.07 Mbp. The genome sequence was then analyzed together with the other two ST201 strains VL-0104 and VL-0391 and compared to the epidemic 027/ST1 and 078/ST11 strains. Phylogenetic analysis demonstrated that the ST201 strains belonged to clade 3. Genome size of the three ST201 strains ranged from 4.07 Mb~4.16 Mb, with an average GC content between 28.5%~28.9%. The ST201 genomes contained more than 40 antibiotic resistance genes and 15 of them were predicted to be associated with vancomycin-resistance, suggesting that they may have a strong antibiotic resistance. The ST201 strains contained a typical clade 3 specific PaLoc with a Tn6218 element inserted, and those genes harbored on their PaLoc that participated in the toxin expression and regulation were highly homologues to the epidemic 027 and 078 strains, with the exception of tcdC. A truncated TcdC was found in the ST201 strains, which is suggestive to have a contribution to the toxin production of the ST201 strains. In addition, the ST201 strains contained intact binary toxin coding and regulation genes, which is also proposed to contribute to the virulence. Genome comparison of the ST201 strains with the epidemic 027 and 078 strain identified 641 genes specific for the C. difficile ST201, and a number of them were predicted as fitness and virulence associated genes. The identification of those genes also contributes to the pathogenesis of the ST201 strain. To our knowledge, this is the first study that the genome sequence of C. difficile ST201 was discussed in detail, and the present study would have a contribution to understanding the pathogenesis basis of C. difficile ST201.

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Section: Discussionmentioning

confidence: 99%

Genome Characterization of a Novel Binary Toxin-Positive Strain of <em>Clostridium difficile</em> and Comparison with the Epidemic 027 and 078 Strains

Peng¹,

Han²,

Meng³

et al. 2017

Preprint

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“…This activates a cascade of proinflammatory cytokines such as TNF-α, IL-23, IL-1β, and interferon-γ, leading to apoptosis of gut epithelial cells and increased permeability of the intestinal mucosa, preceding disease worsening and progression. 31, 32 In the active state of IBD, reports have shown that the innate immune system is activated and responds by secreting a host of proinflammatory cytokines such as IL-1β, IL-6, IL-8, and TNF-α, amplifying the inflammatory response and ultimately resulting in tissue damage. 33, 34 In this study, the amounts of TNF-α in the tissue were elevated in the IBD group, but were significantly increased in the CDI and IBD group, which may be associated with the increased severity of the concurrent diseases.…”

Section: Discussionmentioning

confidence: 99%

Mice with Inflammatory Bowel Disease are Susceptible toClostridium difficileInfection With Severe Disease Outcomes

Zhou

Hamza

Fleur

et al. 2018

Inflammatory Bowel Diseases

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Background Over the past several decades, there has been a significant increase in the incidence of Clostridium difficile infection (CDI) in patients suffering from inflammatory bowel disease (IBD). However, a wild-type animal model is not available to study these comorbid diseases. Methods We evaluated the susceptibility to CDI of mice with dextran sulfate sodium salt (DSS)-induced colitis (IBD mice) with or without antibiotic exposure; we examined the histopathology and cytokine response in the concomitant diseases after the model was created. Results No CDI occurs in healthy control mice, wherease the incidence of CDI in IBD mice is 40%; however, in IBD mice that received antibiotics, the incidence of CDI is 100% and the disease is accompanied by high levels of toxins in the mouse feces and sera. Compared to IBD and CDI alone, those IBD mice infected with C. difficile have more severe symptoms, toxemia, histopathological damage, and higher mortality. Moreover, several proinflammatory cytokines and chemokines are significantly elevated in the colon tissues from IBD mice infected with C. difficile. Conclusions We, for the first time, demonstrate in an animal model that mice with dextran sulfate sodium induced-inflammatory bowel disease are significantly more susceptible to C. difficile infection, and that the bacterial infection led to more severe disease and death. These findings are consistent with clinical observations, thus, the animal model will permit us to study the pathogenesis of these concurrent diseases and to develop therapeutic strategies against the comorbidity of IBD and CDI.

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“…Strains of the ribotype 027 lineage have often been described as “hypervirulent” (11, 15). Studies have pointed to increased toxin production (16), production of a binary toxin (17), fluoroquinolone resistance (14), increased frequency of sporulation (18), enhanced ecological fitness (19) and a higher correlation with recurrent infection (20, 21) as potential mechanisms that led to increased incidence and/or severity of infections associated with ribotype 027 strains. However, some “hypervirulent” attributes of ribotype 027 vary across strains (e.g., degree of toxin production and sporulation (22)) or are found in ribotypes not typically associated with increased disease severity (e.g., fluoroquinolone resistance (23)), making it difficult to pinpoint specific mechanisms responsible for increased incidence and/or severity of infection with ribotype 027 strains.…”

Section: History Of C Difficile Infectionmentioning

confidence: 99%

Control of Clostridium difficile Infection by Defined Microbial Communities

Collins

Auchtung

2017

Microbiol Spectr

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Summary Each year in the United States, billions of dollars are spent combating almost half a million Clostridium difficile infections (CDI) and trying to reduce the ~29,000 patient deaths where C. difficile has an attributed role (1). In Europe, disease prevalence varies by country and level of surveillance, though yearly costs are estimated at €3 billion (2). One factor contributing to the significant healthcare burden of C. difficile is the relatively high frequency of recurrent C. difficile infections(3). Recurrent C. difficile infection (rCDI), i.e., a second episode of symptomatic CDI occurring within eight weeks of successful initial CDI treatment, occurs in ~25% of patients with 35-65% of these patients experiencing multiple episodes of recurrent disease(4, 5). Using microbial communities to treat rCDI, either as whole fecal transplants or as defined consortia of bacterial isolates have shown great success (in the case of fecal transplants) or potential promise (in the case of defined consortia of isolates). This review will briefly summarize the epidemiology and physiology of C. difficile infection, describe our current understanding of how fecal microbiota transplants treat recurrent CDI, and outline potential ways through which that knowledge can be used to rationally-design and test alternative microbe-based therapeutics.

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The binary toxin CDT enhances Clostridium difficile virulence by suppressing protective colonic eosinophilia

Cited by 153 publications

References 52 publications

Genome Characterization of a Novel Binary Toxin-Positive Strain of <em>Clostridium difficile</em> and Comparison with the Epidemic 027 and 078 Strains

Genome Characterization of a Novel Binary Toxin-Positive Strain of <em>Clostridium difficile</em> and Comparison with the Epidemic 027 and 078 Strains

Mice with Inflammatory Bowel Disease are Susceptible toClostridium difficileInfection With Severe Disease Outcomes

Control of Clostridium difficile Infection by Defined Microbial Communities

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