Dataset Information

Ribotype Classification of Clostridioides difficile Isolates Is Not Predictive of the Amino Acid Sequence Diversity of the Toxin Virulence Factors TcdA and TcdB.

ABSTRACT: Clostridioides (Clostridium) difficile is the most commonly recognized cause of infectious diarrhea in healthcare settings. Currently there is no vaccine to prevent initial or recurrent C. difficile infection (CDI). Two large clostridial toxins, TcdA and TcdB, are the primary virulence factors for CDI. Immunological approaches to prevent CDI include antibody-mediated neutralization of the cytotoxicity of these toxins. An understanding of the sequence diversity of the two toxins expressed by disease causing isolates is critical for the interpretation of the immune response to the toxins. In this study, we determined the whole genome sequence (WGS) of 478 C. difficile isolates collected in 12 countries between 2004 and 2018 to probe toxin variant diversity. A total of 44 unique TcdA variants and 37 unique TcdB variants were identified. The amino acid sequence conservation among the TcdA variants (?98%) is considerably greater than among the TcdB variants (as low as 86.1%), suggesting that different selection pressures may have contributed to the evolution of the two toxins. Phylogenomic analysis of the WGS data demonstrate that isolates grouped together based on ribotype or MLST code for multiple different toxin variants. These findings illustrate the importance of determining not only the ribotype but also the toxin sequence when evaluating strain coverage using vaccine strategies that target these virulence factors. We recommend that toxin variant type and sequence type (ST), be used together with ribotype data to provide a more comprehensive strain classification scheme for C. difficile surveillance during vaccine development objectives.

SUBMITTER: Li Z

PROVIDER: S-EPMC7318873 | biostudies-literature | 2020

REPOSITORIES: biostudies-literature

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Ribotype Classification of Clostridioides difficile Isolates Is Not Predictive of the Amino Acid Sequence Diversity of the Toxin Virulence Factors TcdA and TcdB.

Li Zhenghui Z Lee Kwok K Rajyaguru Urvi U Jones C Hal CH Janezic Sandra S Rupnik Maja M Anderson Annaliesa S AS Liberator Paul P

Frontiers in microbiology 20200619

Clostridioides (Clostridium) difficile is the most commonly recognized cause of infectious diarrhea in healthcare settings. Currently there is no vaccine to prevent initial or recurrent C. difficile infection (CDI). Two large clostridial toxins, TcdA and TcdB, are the primary virulence factors for CDI. Immunological approaches to prevent CDI include antibody-mediated neutralization of the cytotoxicity of these toxins. An understanding of the sequence diversity of the ...[more]

PMID: 32636819

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Project description:Clostridioides difficile causes diarrheal diseases mediated in part by the secreted toxins TcdA and TcdB. C. difficile produces flagella that also contribute to motility and bacterial adherence to intestinal cells during infection. Flagellum expression and toxin gene expression are linked via the flagellar alternative sigma factor, SigD. Recently, we identified a flagellar switch upstream of the early flagellar biosynthesis operon that mediates phase variation of both flagellum and toxin production in C. difficile strain R20291. However, we were unable to detect flagellar switch inversion in C. difficile strain 630, a ribotype 012 strain commonly used in research labs, suggesting that the strain is phase locked. To determine whether a phase-locked flagellar switch is limited to 630 or present more broadly in ribotype 012 strains, we assessed the frequency and phenotypic outcomes of flagellar switch inversion in multiple C. difficile ribotype 012 isolates. The laboratory-adapted strain JIR8094, a derivative of strain 630, and six clinical and environmental isolates were all found to be phase-off, nonmotile, and attenuated for toxin production. We isolated low-frequency motile derivatives of JIR8094 with partial recovery of motility and toxin production and found that additional changes in JIR8094 impact these processes. The clinical and environmental isolates varied considerably in the frequency by which flagellar phase-on derivatives arose, and these derivatives showed fully restored motility and toxin production. Taken together, these results demonstrate heterogeneity in flagellar and toxin phase variation among C. difficile ribotype 012 strains and perhaps other ribotypes, which could impact disease progression and diagnosis.IMPORTANCEC. difficile produces flagella that enhance bacterial motility and secretes toxins that promote diarrheal disease symptoms. Previously, we found that production of flagella and toxins is coregulated via a flippable DNA element termed the flagellar switch, which mediates the phase-variable production of these factors. Here, we evaluate multiple isolates of C. difficile ribotype 012 strains and find them to be primarily flagellar phase off (flg-off state). Some, but not all, of these isolates showed the ability to switch between flg-on and -off states. These findings suggest heterogeneity in the ability of C. difficile ribotype 012 strains to phase-vary flagellum and toxin production, which may broadly apply to pathogenic C. difficile.

Dataset Information

Ribotype Classification of Clostridioides difficile Isolates Is Not Predictive of the Amino Acid Sequence Diversity of the Toxin Virulence Factors TcdA and TcdB.

Publications

Ribotype Classification of <i>Clostridioides difficile</i> Isolates Is Not Predictive of the Amino Acid Sequence Diversity of the Toxin Virulence Factors TcdA and TcdB.

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