Clostridium difficile toxin synthesis is negatively regulated by TcdC

Dupuy, Bruno; Govind, Revathi; Antunes, Ana; Matamouros, Susana

doi:10.1099/jmm.0.47775-0

Cited by 124 publications

(85 citation statements)

References 44 publications

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“…The first one was an 18-bp deletion at positions 330 to 347 in the tcdC, and this mutation pattern was also found in the epidemic 027 strain R20291 (Figure 3). However, this 18-bp in frame mutation has been found to have no effect on toxin production [48]. Instead, previous study reported that a deletion at position 117 in tcdC of the 027/ST1 strains compared to strain 630 resulted in the formation of a stop codon and truncation of the protein, and then caused increased toxin production further [49].…”

Section: Discussionmentioning

confidence: 93%

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: 93%

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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“…6 The third gene, tcdE, codes for a protein (TcdE) which shares similarity to phage holin proteins, and may be involved in toxin secretion. 7 The entire PaLoc element is 19.6 kb in size and, therefore, represents an investment by the organism in terms of its continued maintenance in the genome (Fig. 1).…”

Section: Toxin a And Toxin B In Diseasementioning

confidence: 99%

Both, toxin A and toxin B, are important inClostridium difficileinfection.

2011

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T he bacterium Clostridium difficile is the leading cause of healthcare associated diarrhoea in the developed world and thus presents a major financial burden. The main virulence factors of C. difficile are two large toxins, A and B. Over the years there has been some debate over the respective roles and importance of these two toxins. To address this, we recently constructed stable toxin mutants of C. difficile and found that they were virulent if either toxin A or toxin B was functional. This underlined the importance of each toxin and the necessity to consider both when developing countermeasures against Clostridium difficile infection (CDI). In this article we discuss our findings in the context of previous work and outline some of the challenges which face the field as a result. IntroductionIn recent years Clostridium difficile infection (CDI) has emerged as the leading cause of healthcare associated diarrhoea in the developed world. The endospores of this Gram-positive anaerobe are widely distributed in the environment and their ingestion by hospitalised patients with a disrupted gut microflora, a common consequence of antibiotic treatment, leads to colonisation and subsequent disease. 1-3The clinical symptoms of CDI can range from asymptomatic carriage to a mild selflimiting or severe diarrhoea which may progress to the potentially fatal conditions of pseudomembranous colitis and/ or toxic megacolon. In most developed countries, the incidence of CDI continues to increase, concomitant with the emergence of so-called 'hyper-virulent' strains, responsible for increased severity of CDI and a rise in fatalities. In England and Wales, for example, where the mortality rates attributable to CDI are apparently falling, C. difficile still killed almost 4,000 people in 2009 alone. This upsurge in the incidence of CDI has placed a large financial burden on healthcare systems worldwide. 2 Toxin A and Toxin B in DiseaseTwo main virulence factors, toxin A and toxin B, have been described for C. difficile. The two encoding genes, tcdA and tcdB, respectively, form part of a well defined pathogenicity locus (PaLoc) (Fig. 1). The locus also encompasses three ancillary genes. The tcdR gene encodes an alternative sigma factor (TcdR) responsible for the transcription of tcdA and tcdB.4,5 A second gene tcdC, is suggested to encode an antisigma factor (TcdC) which represses toxin production by directly interacting with TcdR or TcdR-containing RNA polymerase. 6 The third gene, tcdE, codes for a protein (TcdE) which shares similarity to phage holin proteins, and may be involved in toxin secretion. 7 The entire PaLoc element is 19.6 kb in size and, therefore, represents an investment by the organism in terms of its continued maintenance in the genome (Fig. 1).The function of the toxins themselves has been studied extensively and their mode of action is now well understood. Both are cytotoxic and belong to the family of large clostridial toxins, capable of inactivating Rho-GTPases and leading to www.landesbioscience.com Gut Microbes...

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“…1A). 8,9 TcdR functions as an alternative RNA polymerase sigma factor, and thus behaves as a positive regulator of toxin gene expression. 10 In contrast, TcdC was initially thought to serve as a negative regulator of toxin production, destabilising the TcdR-holoenzyme, thus hindering transcription of the PaLoc.…”

Section: Roles Of C Difficile Toxin Genes and Diseasementioning

confidence: 99%