Development of an Effective Nontoxigenic Clostridioides difficile–Based Oral Vaccine against C. difficile Infection
ABSTRACT The symptoms of Clostridioides difficile infection (CDI) are largely attributed to two C. difficile toxins, TcdA and TcdB. Significant efforts have been devoted to developing vaccines targeting both toxins through parenteral immunization routes. Recently, we generated a novel chimeric prote...
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| Format: | Article |
| Language: | English |
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American Society for Microbiology
2022-06-01
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| Series: | Microbiology Spectrum |
| Subjects: | |
| Online Access: | https://journals.asm.org/doi/10.1128/spectrum.00263-22 |
| _version_ | 1828833214940053504 |
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| author | Shaohui Wang Duolong Zhu Xingmin Sun |
| author_facet | Shaohui Wang Duolong Zhu Xingmin Sun |
| author_sort | Shaohui Wang |
| collection | DOAJ |
| description | ABSTRACT The symptoms of Clostridioides difficile infection (CDI) are largely attributed to two C. difficile toxins, TcdA and TcdB. Significant efforts have been devoted to developing vaccines targeting both toxins through parenteral immunization routes. Recently, we generated a novel chimeric protein (designated Tcd169), comprised of the glucosyltransferase domain (GT), the cysteine protease domain (CPD), and the receptor binding domain (RBD) of TcdB, and the RBD of TcdA. Parenteral immunizations with Tcd169 provide mice effective protection against infection with a ribotype (RT) 027 C. difficile strain. In this study, we expressed Tcd169 in a nontoxigenic C. difficile CCUG37785 strain (designated NTCD), resulting in strain NTCD_Tcd169 to develop an oral vaccine that can target both C. difficile toxins and colonization/adhesion factors. Oral immunizations with NTCD_Tcd169 spores induced systematic and mucosal antibody responses against, not only both toxins, but also C. difficile flagellins (FliC/FliD). Intriguingly yet importantly, anti-Tcd169 sera raised against Tcd169 protein were significantly cross-reactive with FliC/FliD and two surface layer proteins (SlpA and Cwp2). Oral immunizations with NTCD_Tcd169 spores provided mice effective protection against infection with a hypervirulent RT027 C. difficile strain R20291and significantly reduced R20291spore numbers in feces compared with NTCD or PBS immunized mice. These results imply that the genetically modified, nontoxigenic C. difficile strain expressing Tcd169 may represent a novel mucosal vaccine candidate against CDI. IMPORTANCE Clostridioides difficile is an enteric pathogen, and symptoms of C. difficile infection (CDI) are mainly by two exotoxins TcdA and TcdB. Active vaccination is cost-effective approach to prevent CDI and high rates of recurrence. Ideally, vaccines should target both C. difficile toxins and cell/spore colonization. In this study, we expressed immunodominant fragments of TcdA and TcdB (i.e., Tcd169) in a nontoxigenic C. difficile CCUG37785 strain, generating a promising oral/mucosal vaccine candidate against CDI, by targeting both toxins and colonization of pathogenic C. difficile strains. Importantly, anti-Tcd169 sera raised against Tcd169 protein were significantly cross-reactive with FliC/FliD and two surface layer proteins (SlpA and Cwp2), and all of which are involved in C. difficile adhesion/colonization in vitro and in vivo. |
| first_indexed | 2024-12-12T17:13:42Z |
| format | Article |
| id | doaj.art-bbb97c1c4bd343128096d485bd97fdbc |
| institution | Directory Open Access Journal |
| issn | 2165-0497 |
| language | English |
| last_indexed | 2024-12-12T17:13:42Z |
| publishDate | 2022-06-01 |
| publisher | American Society for Microbiology |
| record_format | Article |
| series | Microbiology Spectrum |
| spelling | doaj.art-bbb97c1c4bd343128096d485bd97fdbc2022-12-22T00:17:50ZengAmerican Society for MicrobiologyMicrobiology Spectrum2165-04972022-06-0110310.1128/spectrum.00263-22Development of an Effective Nontoxigenic Clostridioides difficile–Based Oral Vaccine against C. difficile InfectionShaohui Wang0Duolong Zhu1Xingmin Sun2Department of Molecular Medicine, Morsani College of Medicine, University of South Florida, Tampa, Florida, USADepartment of Molecular Medicine, Morsani College of Medicine, University of South Florida, Tampa, Florida, USADepartment of Molecular Medicine, Morsani College of Medicine, University of South Florida, Tampa, Florida, USAABSTRACT The symptoms of Clostridioides difficile infection (CDI) are largely attributed to two C. difficile toxins, TcdA and TcdB. Significant efforts have been devoted to developing vaccines targeting both toxins through parenteral immunization routes. Recently, we generated a novel chimeric protein (designated Tcd169), comprised of the glucosyltransferase domain (GT), the cysteine protease domain (CPD), and the receptor binding domain (RBD) of TcdB, and the RBD of TcdA. Parenteral immunizations with Tcd169 provide mice effective protection against infection with a ribotype (RT) 027 C. difficile strain. In this study, we expressed Tcd169 in a nontoxigenic C. difficile CCUG37785 strain (designated NTCD), resulting in strain NTCD_Tcd169 to develop an oral vaccine that can target both C. difficile toxins and colonization/adhesion factors. Oral immunizations with NTCD_Tcd169 spores induced systematic and mucosal antibody responses against, not only both toxins, but also C. difficile flagellins (FliC/FliD). Intriguingly yet importantly, anti-Tcd169 sera raised against Tcd169 protein were significantly cross-reactive with FliC/FliD and two surface layer proteins (SlpA and Cwp2). Oral immunizations with NTCD_Tcd169 spores provided mice effective protection against infection with a hypervirulent RT027 C. difficile strain R20291and significantly reduced R20291spore numbers in feces compared with NTCD or PBS immunized mice. These results imply that the genetically modified, nontoxigenic C. difficile strain expressing Tcd169 may represent a novel mucosal vaccine candidate against CDI. IMPORTANCE Clostridioides difficile is an enteric pathogen, and symptoms of C. difficile infection (CDI) are mainly by two exotoxins TcdA and TcdB. Active vaccination is cost-effective approach to prevent CDI and high rates of recurrence. Ideally, vaccines should target both C. difficile toxins and cell/spore colonization. In this study, we expressed immunodominant fragments of TcdA and TcdB (i.e., Tcd169) in a nontoxigenic C. difficile CCUG37785 strain, generating a promising oral/mucosal vaccine candidate against CDI, by targeting both toxins and colonization of pathogenic C. difficile strains. Importantly, anti-Tcd169 sera raised against Tcd169 protein were significantly cross-reactive with FliC/FliD and two surface layer proteins (SlpA and Cwp2), and all of which are involved in C. difficile adhesion/colonization in vitro and in vivo.https://journals.asm.org/doi/10.1128/spectrum.00263-22nontoxigenic Clostridioides difficileClostridioides difficile infectionchimeric proteinvaccinesporeoral immunization |
| spellingShingle | Shaohui Wang Duolong Zhu Xingmin Sun Development of an Effective Nontoxigenic Clostridioides difficile–Based Oral Vaccine against C. difficile Infection Microbiology Spectrum nontoxigenic Clostridioides difficile Clostridioides difficile infection chimeric protein vaccine spore oral immunization |
| title | Development of an Effective Nontoxigenic Clostridioides difficile–Based Oral Vaccine against C. difficile Infection |
| title_full | Development of an Effective Nontoxigenic Clostridioides difficile–Based Oral Vaccine against C. difficile Infection |
| title_fullStr | Development of an Effective Nontoxigenic Clostridioides difficile–Based Oral Vaccine against C. difficile Infection |
| title_full_unstemmed | Development of an Effective Nontoxigenic Clostridioides difficile–Based Oral Vaccine against C. difficile Infection |
| title_short | Development of an Effective Nontoxigenic Clostridioides difficile–Based Oral Vaccine against C. difficile Infection |
| title_sort | development of an effective nontoxigenic clostridioides difficile based oral vaccine against c difficile infection |
| topic | nontoxigenic Clostridioides difficile Clostridioides difficile infection chimeric protein vaccine spore oral immunization |
| url | https://journals.asm.org/doi/10.1128/spectrum.00263-22 |
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