Dataset Information

Epidemic ribotypes of Clostridium (now Clostridioides) difficile are likely to be more virulent than non-epidemic ribotypes in animal models.

ABSTRACT: BACKGROUND:Clostridioides difficile infections have become more frequently diagnosed and associated with greater disease severity, which has resulted in an increase burden on the healthcare system. These increases are attributed to the increased prevalence of hypervirulent strains encompassing select ribotypes. These epidemic ribotypes were characterized as hypervirulent due to higher in vitro spore and toxin production, as well as increased incidence, severity and mortality within patients. However, it is unclear whether epidemic ribotypes are truly more virulent than non-epidemic ribotypes in vivo. Furthermore, there is conflicting evidence about the ability of a strain's in vitro phenotype to be predictive of their in vivo virulence. The goals of the current studies were to determine if epidemic ribotypes are more virulent than other ribotypes in animal models, and whether the in vitro virulence phenotype of an isolate or ribotype predict in vivo virulence. RESULTS:To determine if epidemic strains were truly more virulent than other non-epidemic strains, the in vivo virulence of 13 C. difficile isolates (7 non-epidemic and 6 epidemic ribotype isolates) were determined in murine and hamster models of CDI. The isolates of epidemic ribotype of C. difficile were found to be more virulent in both the murine and hamster models than non-epidemic isolates. In particular, the group of epidemic ribotypes of C. difficile had lower LD50 values in hamsters. The increased severity of disease was associated with higher levels of Toxin A and Toxin B production found in fecal samples, but not numbers of organisms recovered. The isolates were further characterized for their in vitro virulence phenotypes, e.g. toxin production, growth rates, spore formation and adherence of spores to intestinal epithelial cell lines. Although there were higher levels of toxins produced and greater adherence for the group of epidemic ribotypes, the in vitro profiles of individual isolates were not always predictive of their in vivo virulence. CONCLUSIONS:Overall, the group of epidemic ribotypes of C. difficile were more virulent in vivo despite individual isolates having similar phenotypes to the non-epidemic isolates in vitro.

SUBMITTER: Vitucci JC

PROVIDER: S-EPMC7003423 | biostudies-literature | 2020 Feb

REPOSITORIES: biostudies-literature

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Epidemic ribotypes of Clostridium (now Clostridioides) difficile are likely to be more virulent than non-epidemic ribotypes in animal models.

Vitucci John C JC Pulse Mark M Tabor-Simecka Leslie L Simecka Jerry J

BMC microbiology 20200205 1

<h4>Background</h4>Clostridioides difficile infections have become more frequently diagnosed and associated with greater disease severity, which has resulted in an increase burden on the healthcare system. These increases are attributed to the increased prevalence of hypervirulent strains encompassing select ribotypes. These epidemic ribotypes were characterized as hypervirulent due to higher in vitro spore and toxin production, as well as increased incidence, severity and mortality within patie ...[more]

PMID: 32024477

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Project description:Clostridioides difficile is a gram-positive spore-forming pathogen that commonly causes diarrheal infections in the developed world. Although C. difficile is a genetically diverse species, certain ribotypes are overrepresented in human infections. It is unknown if metabolic adaptations are essential for the emergence of these epidemic ribotypes. Here, we tested carbon substrate utilization by 88 C. difficile isolates and looked for differences in growth between 22 ribotypes. By profiling clinical isolates, we assert that C. difficile is a generalist species capable of growing on a variety of carbon substrates. Further, C. difficile strains clustered by phylogenetic relationship and displayed ribotype-specific and clade-specific metabolic capabilities. Surprisingly, we observed that two emerging lineages, ribotypes 023 and 255, have divergent metabolic phenotypes. In addition, although C. difficile Clade 5 is the most evolutionary distant clade and often detected in animals, it displayed more robust growth on simple dietary sugars than Clades 1-4. Altogether, our results corroborate the generalist metabolic strategy of C. difficile and demonstrate lineage-specific metabolic capabilities. In addition, our approach can be adapted to the study of additional pathogens to ascertain their metabolic niches in the gut.ImportanceThe gut pathogen Clostridioides difficile utilizes a wide range of carbon sources. Microbial communities can be rationally designed to combat C. difficile by depleting its preferred nutrients in the gut. However, C. difficile is genetically diverse with hundreds of identified ribotypes and most of its metabolic studies were performed with lab-adapted strains. Here, we profiled carbon metabolism by a myriad of C. difficile clinical isolates. While the metabolic capabilities of these isolates clustered by their genetic lineage, we observed surprising metabolic divergence between two emerging lineages. We also found that the most genetically distant clade grew robustly on simple dietary sugars, posing intriguing questions about the adaptation of C. difficile to the human gut. Altogether, our results underscore the importance of considering the metabolic diversity of pathogens in the study of their evolution and the rational design of therapeutic interventions.

Project description:Comparative analysis of Clostridioides difficile whole-genome sequencing (WGS) data enables fine scaled investigation of transmission and is increasingly becoming part of routine surveillance. However, these analyses are constrained by the computational requirements of the large volumes of data involved. By decomposing WGS reads or assemblies into k-mers and using the dimensionality reduction technique MinHash, it is possible to rapidly approximate genomic distances without alignment. Here we assessed the performance of MinHash, as implemented by sourmash, in predicting single nucleotide differences between genomes (SNPs) and C. difficile ribotypes (RTs). For a set of 1905 diverse C. difficile genomes (differing by 0-168 519 SNPs), using sourmash to screen for closely related genomes, at a sensitivity of 100 % for pairs ≤10 SNPs, sourmash reduced the number of pairs from 1 813 560 overall to 161 934, i.e. by 91 %, with a positive predictive value of 32 % to correctly identify pairs ≤10 SNPs (maximum SNP distance 4144). At a sensitivity of 95 %, pairs were reduced by 94 % to 108 266 and PPV increased to 45 % (maximum SNP distance 1009). Increasing the MinHash sketch size above 2000 produced minimal performance improvement. We also explored a MinHash similarity-based ribotype prediction method. Genomes with known ribotypes (n=3937) were split into a training set (2937) and test set (1000) randomly. The training set was used to construct a sourmash index against which genomes from the test set were compared. If the closest five genomes in the index had the same ribotype this was taken to predict the searched genome's ribotype. Using our MinHash ribotype index, predicted ribotypes were correct in 780/1000 (78 %) genomes, incorrect in 20 (2 %), and indeterminant in 200 (20 %). Relaxing the classifier to 4/5 closest matches with the same RT improved the correct predictions to 87 %. Using MinHash it is possible to subsample C. difficile genome k-mer hashes and use them to approximate small genomic differences within minutes, significantly reducing the search space for further analysis.

Dataset Information

Epidemic ribotypes of Clostridium (now Clostridioides) difficile are likely to be more virulent than non-epidemic ribotypes in animal models.

Publications

Epidemic ribotypes of Clostridium (now Clostridioides) difficile are likely to be more virulent than non-epidemic ribotypes in animal models.

Similar Datasets

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