Ribotype Classification of Clostridioides difficile Isolates Is Not Predictive of the Amino Acid Sequence Diversity of the Toxin Virulence Factors TcdA and TcdB
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 C...
| Main Authors: | , , , , , , , |
|---|---|
| Format: | Article |
| Language: | English |
| Published: |
Frontiers Media S.A.
2020-06-01
|
| Series: | Frontiers in Microbiology |
| Subjects: | |
| Online Access: | https://www.frontiersin.org/article/10.3389/fmicb.2020.01310/full |
| _version_ | 1811285740528599040 |
|---|---|
| author | Zhenghui Li Kwok Lee Urvi Rajyaguru C. Hal Jones Sandra Janezic Sandra Janezic Maja Rupnik Maja Rupnik Annaliesa S. Anderson Paul Liberator |
| author_facet | Zhenghui Li Kwok Lee Urvi Rajyaguru C. Hal Jones Sandra Janezic Sandra Janezic Maja Rupnik Maja Rupnik Annaliesa S. Anderson Paul Liberator |
| author_sort | Zhenghui Li |
| collection | DOAJ |
| description | 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. |
| first_indexed | 2024-04-13T02:49:23Z |
| format | Article |
| id | doaj.art-41eb581e31e045218576ad060d1de2e0 |
| institution | Directory Open Access Journal |
| issn | 1664-302X |
| language | English |
| last_indexed | 2024-04-13T02:49:23Z |
| publishDate | 2020-06-01 |
| publisher | Frontiers Media S.A. |
| record_format | Article |
| series | Frontiers in Microbiology |
| spelling | doaj.art-41eb581e31e045218576ad060d1de2e02022-12-22T03:05:54ZengFrontiers Media S.A.Frontiers in Microbiology1664-302X2020-06-011110.3389/fmicb.2020.01310519446Ribotype Classification of Clostridioides difficile Isolates Is Not Predictive of the Amino Acid Sequence Diversity of the Toxin Virulence Factors TcdA and TcdBZhenghui Li0Kwok Lee1Urvi Rajyaguru2C. Hal Jones3Sandra Janezic4Sandra Janezic5Maja Rupnik6Maja Rupnik7Annaliesa S. Anderson8Paul Liberator9Vaccine Research and Development, Pfizer Inc., Pearl River, NY, United StatesVaccine Research and Development, Pfizer Inc., Pearl River, NY, United StatesVaccine Research and Development, Pfizer Inc., Pearl River, NY, United StatesVaccine Research and Development, Pfizer Inc., Pearl River, NY, United StatesNational Laboratory for Health, Environment and Food, Maribor, SloveniaFaculty of Medicine, University of Maribor, Maribor, SloveniaNational Laboratory for Health, Environment and Food, Maribor, SloveniaFaculty of Medicine, University of Maribor, Maribor, SloveniaVaccine Research and Development, Pfizer Inc., Pearl River, NY, United StatesVaccine Research and Development, Pfizer Inc., Pearl River, NY, United StatesClostridioides (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.https://www.frontiersin.org/article/10.3389/fmicb.2020.01310/fullClostridioides difficileClostridium difficileTcdATCDBvaccineswhole genome sequencing |
| spellingShingle | Zhenghui Li Kwok Lee Urvi Rajyaguru C. Hal Jones Sandra Janezic Sandra Janezic Maja Rupnik Maja Rupnik Annaliesa S. Anderson Paul Liberator Ribotype Classification of Clostridioides difficile Isolates Is Not Predictive of the Amino Acid Sequence Diversity of the Toxin Virulence Factors TcdA and TcdB Frontiers in Microbiology Clostridioides difficile Clostridium difficile TcdA TCDB vaccines whole genome sequencing |
| title | Ribotype Classification of Clostridioides difficile Isolates Is Not Predictive of the Amino Acid Sequence Diversity of the Toxin Virulence Factors TcdA and TcdB |
| title_full | Ribotype Classification of Clostridioides difficile Isolates Is Not Predictive of the Amino Acid Sequence Diversity of the Toxin Virulence Factors TcdA and TcdB |
| title_fullStr | Ribotype Classification of Clostridioides difficile Isolates Is Not Predictive of the Amino Acid Sequence Diversity of the Toxin Virulence Factors TcdA and TcdB |
| title_full_unstemmed | Ribotype Classification of Clostridioides difficile Isolates Is Not Predictive of the Amino Acid Sequence Diversity of the Toxin Virulence Factors TcdA and TcdB |
| title_short | Ribotype Classification of Clostridioides difficile Isolates Is Not Predictive of the Amino Acid Sequence Diversity of the Toxin Virulence Factors TcdA and TcdB |
| title_sort | ribotype classification of clostridioides difficile isolates is not predictive of the amino acid sequence diversity of the toxin virulence factors tcda and tcdb |
| topic | Clostridioides difficile Clostridium difficile TcdA TCDB vaccines whole genome sequencing |
| url | https://www.frontiersin.org/article/10.3389/fmicb.2020.01310/full |
| work_keys_str_mv | AT zhenghuili ribotypeclassificationofclostridioidesdifficileisolatesisnotpredictiveoftheaminoacidsequencediversityofthetoxinvirulencefactorstcdaandtcdb AT kwoklee ribotypeclassificationofclostridioidesdifficileisolatesisnotpredictiveoftheaminoacidsequencediversityofthetoxinvirulencefactorstcdaandtcdb AT urvirajyaguru ribotypeclassificationofclostridioidesdifficileisolatesisnotpredictiveoftheaminoacidsequencediversityofthetoxinvirulencefactorstcdaandtcdb AT chaljones ribotypeclassificationofclostridioidesdifficileisolatesisnotpredictiveoftheaminoacidsequencediversityofthetoxinvirulencefactorstcdaandtcdb AT sandrajanezic ribotypeclassificationofclostridioidesdifficileisolatesisnotpredictiveoftheaminoacidsequencediversityofthetoxinvirulencefactorstcdaandtcdb AT sandrajanezic ribotypeclassificationofclostridioidesdifficileisolatesisnotpredictiveoftheaminoacidsequencediversityofthetoxinvirulencefactorstcdaandtcdb AT majarupnik ribotypeclassificationofclostridioidesdifficileisolatesisnotpredictiveoftheaminoacidsequencediversityofthetoxinvirulencefactorstcdaandtcdb AT majarupnik ribotypeclassificationofclostridioidesdifficileisolatesisnotpredictiveoftheaminoacidsequencediversityofthetoxinvirulencefactorstcdaandtcdb AT annaliesasanderson ribotypeclassificationofclostridioidesdifficileisolatesisnotpredictiveoftheaminoacidsequencediversityofthetoxinvirulencefactorstcdaandtcdb AT paulliberator ribotypeclassificationofclostridioidesdifficileisolatesisnotpredictiveoftheaminoacidsequencediversityofthetoxinvirulencefactorstcdaandtcdb |