Precise Manipulation of the Clostridium difficile Chromosome Reveals a Lack of Association between the
            <i>tcdC</i>
            Genotype and Toxin Production

Cartman, Stephen T.; Kelly, Michelle L.; Heeg, Daniela; Heap, John; Minton, Nigel P.

doi:10.1128/aem.00249-12

Cited by 216 publications

(231 citation statements)

References 39 publications

(46 reference statements)

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“…The extent of virulence in the complemented tcdC ϩ strain was almost identical to that of C. difficile strain 630, which endogenously expresses normal TcdC, further indicating that the lesion in tcdC accounted for the increased virulence in the hypervirulent strain. In contrast to these findings, other work has found that allelic exchange using intact tcdC to replace the mutant form of tcdC does not alter levels of toxin production in a hypervirulent strain (185). Similarly, allelic replacement of an unmutated tcdC gene with a tcdC gene carrying the mutation did not cause the 630 strain to express larger amounts of the toxin (186).…”

Section: Factors Accounting For Epidemics and Hypervirulence Of Nap1/contrasting

confidence: 43%

Variations in Virulence and Molecular Biology among Emerging Strains of Clostridium difficile

Hunt

Ballard

2013

Microbiol Mol Biol Rev

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SUMMARY Clostridium difficile is a Gram-positive, spore-forming organism which infects and colonizes the large intestine, produces potent toxins, triggers inflammation, and causes significant systemic complications. Treating C. difficile infection (CDI) has always been difficult, because the disease is both caused and resolved by antibiotic treatment. For three and a half decades, C. difficile has presented a treatment challenge to clinicians, and the situation took a turn for the worse about 10 years ago. An increase in epidemic outbreaks related to CDI was first noticed around 2003, and these outbreaks correlated with a sudden increase in the mortality rate of this illness. Further studies discovered that these changes in CDI epidemiology were associated with the rapid emergence of hypervirulent strains of C. difficile , now collectively referred to as NAP1/BI/027 strains. The discovery of new epidemic strains of C. difficile has provided a unique opportunity for retrospective and prospective studies that have sought to understand how these strains have essentially replaced more historical strains as a major cause of CDI. Moreover, detailed studies on the pathogenesis of NAP1/BI/027 strains are leading to new hypotheses on how this emerging strain causes severe disease and is more commonly associated with epidemics. In this review, we provide an overview of CDI, discuss critical mechanisms of C. difficile virulence, and explain how differences in virulence-associated factors between historical and newly emerging strains might explain the hypervirulence exhibited by this pathogen during the past decade.

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Section: Factors Accounting For Epidemics and Hypervirulence Of Nap1/contrasting

confidence: 43%

Variations in Virulence and Molecular Biology among Emerging Strains of Clostridium difficile

Hunt

Ballard

2013

Microbiol Mol Biol Rev

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“…These mutations cause premature stops, and this truncation is believed to cause toxin overproduction (6,7). However, this assumption was challenged by recent studies showing no significant difference in toxin production between hypervirulent and nonhypervirulent C. difficile strains, and no association of the tcdC genotype and toxin production (8,9).…”

mentioning

confidence: 81%

Phenotypic and Genotypic Analysis of Clostridium difficile Isolates: a Single-Center Study

et al. 2014

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f Clostridium difficile infections (CDI) are a growing concern in North America, because of their increasing incidence and severity. Using integrated approaches, we correlated pathogen genotypes and host clinical characteristics for 46 C. difficile infections in a tertiary care medical center during a 6-month interval from January to June 2010. Multilocus sequence typing (MLST) demonstrated 21 known and 2 novel sequence types (STs), suggesting that the institution's C. difficile strains are genetically diverse. ST-1 (which corresponds to pulsed-field gel electrophoresis strain type NAP1/ribotype 027) was the most prevalent (32.6%); 43.5% of the isolates were binary toxin gene positive, of which 75% were ST-1. All strains were ciprofloxacin resistant and metronidazole susceptible, and 8.3% and 13.0% of the isolates were resistant to clindamycin and tetracycline, respectively. The corresponding resistance loci, including potential novel mutations, were identified from the whole-genome sequencing (WGS) of the resistant strains. Core genome single nucleotide polymorphisms (SNPs) determining the phylogenetic relatedness of the 46 strains recapitulated MLST types and provided greater interstrain differentiation. The disease severity was greatest in patients infected with ST-1 and/or binary gene-positive strains, but genome-wide SNP analysis failed to provide additional associations with CDI severity within the same STs. We conclude that MLST and core genome SNP typing result in the same phylogenetic grouping of the 46 C. difficile strains collected in a single hospital. WGS also has the capacity to differentiate those strains within STs and allows the comparison of strains at the individual gene level and at the whole-genome level. The most common C. difficile strain that has emerged in the past decade in North America and some areas in Europe has been classified as 027 by ribotyping, NAP1 by pulsed-field gel electrophoresis (PFGE), BI by restriction endonuclease analysis, and ST-1 by multilocus sequence typing (MLST). ST-1 strains account for half of the sporadic hospital-associated CDI in some settings (5). Some studies have reported that ST-1 strains elaborate C. difficile toxins (TCDs) at high concentrations; its purported hypervirulence is plausibly related to this trait. This strain has single and 18-bp deletions of tcdC, a negative regulator of tcdA and tcdB. These mutations cause premature stops, and this truncation is believed to cause toxin overproduction (6, 7). However, this assumption was challenged by recent studies showing no significant difference in toxin production between hypervirulent and nonhypervirulent C. difficile strains, and no association of the tcdC genotype and toxin production (8, 9).C. difficile strains containing cdtA and cdtB binary toxin genes are associated with greater mortality in their hosts than strains in which these genes are absent (10). However, it is not clear if the binary toxin genes increase the virulence of ST-1 or if they are simply epidemiologic markers of C. difficile...

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“…A poreforming holin is encoded by tcdE, which allows the release of TcdA and TcdB. Literature has suggested that hypervirulent NAP1 C. difficile released more toxin due to decreased expression of tcdC; however, this has come into question due to recent evidence that demonstrates no change in toxin production [54] . Another gene regulator is CodY, which binds and represses tcdR and thus inhibits toxin production, when essential nutrients are not available [55] .…”

Section: Epidemiology and Risk Factors For CDImentioning

confidence: 79%

Gastrointestinal dysbiosis and the use of fecal microbial transplantation inClostridium difficileinfection

Schenck

Beck

MacDonald

2015

WJGP

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The impact of antibiotics on the human gut microbiota is a significant concern. Antibiotic-associated diarrhea has been on the rise for the past few decades with the increasing usage of antibiotics. Clostridium difficile infections (CDI) have become one of the most prominent types of infectious diarrheal disease, with dramatically increased incidence in both the hospital and community setting worldwide. Studies show that variability in the innate host response may in part impact upon CDI severity in patients. That being said, CDI is a disease that shows the most prominent links to alterations to the gut microbiota, in both cause and treatment. With recurrence rates still relatively high, it is important to explore alternative therapies to CDI. Fecal microbiota transplantation (FMT) and other types of bacteriotherapy have become exciting avenues of treatment for CDI. Recent clinical trials have generated excitement for the use of FMT as a therapeutic option for CDI; however, the exact components of the human gut microbiota needed for protection against CDI have remained elusive. Additional investigations on the effects of antibiotics on the human gut microbiota and subsequent CDI will help reduce the socioeconomic burden of CDI and potentially lead to new therapeutic modalities.

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Precise Manipulation of the Clostridium difficile Chromosome Reveals a Lack of Association between the tcdC Genotype and Toxin Production

Cited by 216 publications

References 39 publications

Variations in Virulence and Molecular Biology among Emerging Strains of Clostridium difficile

Variations in Virulence and Molecular Biology among Emerging Strains of Clostridium difficile

Phenotypic and Genotypic Analysis of Clostridium difficile Isolates: a Single-Center Study

Gastrointestinal dysbiosis and the use of fecal microbial transplantation inClostridium difficileinfection

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