Clostridium difficile Toxoid Vaccine Candidate Confers Broad Protection against a Range of Prevalent Circulating Strains in a Nonclinical Setting

Quéméneur, Laurence; Petiot, Nadine; Arnaud-Barbe, Nadège; Hessler, Catherine; Pietrobon, Patricia J. Freda; Londoño-Hayes, Patricia

doi:10.1128/iai.00742-17

Cited by 9 publications

(6 citation statements)

References 49 publications

(59 reference statements)

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“…target the large clostridial toxins, TcdA/TcdB (11), there is nothing approved by the Food and Drug Administration to target the C. difficile toxin (CDT) or the "binary toxin" (12). Other evidence demonstrating an urgency to develop antitoxins targeting the binary toxin include: 1) Patients with binary toxin-containing strains of C. difficile infection show heightened disease severity and reoccurrence (13)(14)(15)(16); 2) strains of having only the C. difficile binary toxin and not TcdA/TcdB (A − B − CDT + ) retain virulence and present as C. difficile infection in the clinic (16,17); and 3) an immunological response in hamsters to a vaccine targeting TcdA/ TcdB and the binary toxin showed much higher efficacy toward challenges from a hypervirulent strain of C. difficile infection (i.e., NAP1) than a vaccine derived only from TcdA/TcdB antigens (12,18). Therefore, to address this unmet medical need, studies of the structure, function, and inhibition of the C. difficile binary toxin are paramount to identifying its vulnerabilities and for developing novel treatments to improve patient outcomes for the most severe cases of C. difficile infection.…”

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confidence: 99%

Structure of the cell-binding component of the Clostridium difficile binary toxin reveals a di-heptamer macromolecular assembly

Godoy‐Ruiz

Adipietro

et al. 2020

Proc. Natl. Acad. Sci. U.S.A.

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Targeting Clostridium difficile infection is challenging because treatment options are limited, and high recurrence rates are common. One reason for this is that hypervirulent C. difficile strains often have a binary toxin termed the C. difficile toxin, in addition to the enterotoxins TsdA and TsdB. The C. difficile toxin has an enzymatic component, termed CDTa, and a pore-forming or delivery subunit termed CDTb. CDTb was characterized here using a combination of single-particle cryoelectron microscopy, X-ray crystallography, NMR, and other biophysical methods. In the absence of CDTa, 2 di-heptamer structures for activated CDTb (1.0 MDa) were solved at atomic resolution, including a symmetric (SymCDTb; 3.14 Å) and an asymmetric form (AsymCDTb; 2.84 Å). Roles played by 2 receptor-binding domains of activated CDTb were of particular interest since the receptor-binding domain 1 lacks sequence homology to any other known toxin, and the receptor-binding domain 2 is completely absent in other well-studied heptameric toxins (i.e., anthrax). For AsymCDTb, a Ca2+ binding site was discovered in the first receptor-binding domain that is important for its stability, and the second receptor-binding domain was found to be critical for host cell toxicity and the di-heptamer fold for both forms of activated CDTb. Together, these studies represent a starting point for developing structure-based drug-design strategies to target the most severe strains of C. difficile.

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confidence: 99%

Structure of the cell-binding component of the Clostridium difficile binary toxin reveals a di-heptamer macromolecular assembly

Godoy‐Ruiz

Adipietro

et al. 2020

Proc. Natl. Acad. Sci. U.S.A.

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“…TcdB2 has enhanced ability to enter host cells, is more cytotoxic, and exhibits wider tissue tropism 54,55 . In contrast to RT027 strains, the PaLoc of RT106 strains is 100% identical to 630 [62][63][64][65] ; thus, these strains encode full-length TcdC and express the TcdB1 toxin variant. Both RT027 and RT106 isolates produce variable amounts of TcdA/TcdB.…”

Section: Discussionmentioning

confidence: 99%

Phylogenomic analysis of Clostridioides difficile ribotype 106 strains reveals novel genetic islands and emergent phenotypes

Roxas

Claus-Walker

et al. 2020

Sci Rep

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Clostridioides difficile infection (CDI) is a major healthcare-associated diarrheal disease. Consistent with trends across the United States, C. difficile RT106 was the second-most prevalent molecular type in our surveillance in Arizona from 2015 to 2018. A representative RT106 strain displayed robust virulence and 100% lethality in the hamster model of acute CDI. We identified a unique 46 KB genomic island (GI1) in all RT106 strains sequenced to date, including those in public databases. GI1 was not found in its entirety in any other C. difficile clade, or indeed, in any other microbial genome; however, smaller segments were detected in Enterococcus faecium strains. Molecular clock analyses suggested that GI1 was horizontally acquired and sequentially assembled over time. GI1 encodes homologs of VanZ and a SrtB-anchored collagen-binding adhesin, and correspondingly, all tested RT106 strains had increased teicoplanin resistance, and a majority displayed collagen-dependent biofilm formation. Two additional genomic islands (GI2 and GI3) were also present in a subset of RT106 strains. All three islands are predicted to encode mobile genetic elements as well as virulence factors. Emergent phenotypes associated with these genetic islands may have contributed to the relatively rapid expansion of RT106 in US healthcare and community settings.

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“…TcdB2 has enhanced ability to enter host cells, is more cytotoxic, and exhibits wider tissue tropism (44, 45). In contrast to RT027 strains, the PaLoc of RT106 strains is 100% identical to 630 (53-56); thus, these strains encode full-length TcdC and express the TcdB1 toxin variant. Both RT027 and RT106 isolates produce variable amounts of TcdA/TcdB.…”

Section: Discussionmentioning

confidence: 99%

Phylogenomic analysis ofClostridiodes difficileribotype 106 strains reveals novel genetic islands and emergent phenotypes

Roxas

Claus-Walker

et al. 2020

Preprint

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27Background: Clostridioides difficile RT106 has emerged as a dominant molecular type 28 in the USA in recent years, but the underlying factors contributing to its predominance 29 remain undefined. As part of our ongoing C. difficile infection (CDI) surveillance in 30 Arizona, we monitored RT106 frequency and characterized the genomic and phenotypic 31 properties of the recovered isolates. 32Results: From 2015-2018, RT106 was the second-most prevalent molecular type 33 isolated from CDI patients in our surveillance. A representative RT106 strain displayed 34 robust virulence and 100% lethality in the hamster model of acute CDI. We identified a 35 unique 46 KB genomic island (GI1) in all RT106 strains, including those in public 36 databases. GI1 was not found in its entirety in any other C. difficile clade, or indeed in any 37 other microbial genome; however, smaller segments were detected in select 38 Enterococcus faecium strains. Molecular clock analyses suggest that GI1 was 39 horizontally acquired and sequentially assembled over time. Consistent with the presence 40 of genes encoding homologs of VanZ and a SrtB-anchored collagen-binding adhesin in 41 GI1, all tested RT106 strains had increased teicoplanin resistance and a majority 42 displayed collagen-dependent biofilm formation. Two additional genomic islands (GI2 and 43 GI3) were also present in a subset of RT106 strains. All three islands have features of 44 mobile genetic elements and encode several putative virulence factors. 45 Conclusions: Consistent with the known genetic plasticity of C. difficile, strains belonging 46 to the RT106 clade harbor unique genetic islands. Correspondingly, emergent phenotypic 47 properties may contribute to the relatively rapid shifts of strain distribution in patient 48 populations. 49 Keywords: Clostridioides difficile, RT106, teicoplanin, VanZ, SrtB-anchored collagen-50 binding adhesin, genomic island 51 52 BACKGROUND 53The Gram-positive and spore-forming anaerobic bacterium Clostridioides difficile 54 (formerly named Clostridium difficile) is a leading cause of antibiotic-associated diarrhea 55 that may be self-limiting, or progress to severe and fulminant (pseudomembranous) colitis 56 or toxic megacolon (1-4). There has been an increased incidence of C. difficile infection 57 (CDI) over the past two decades (5-8) and, in the USA, this coincides with the emergence 58 and spread of ribotype 027 strains [also called RT027 or BI or NAP1 based on the 59 phylogenetic test (9, 10)]. While RT027 remains the most prevalent healthcare-associated 60 C. difficile ribotype, its frequency has been steadily declining (11). Multiple surveillance 61 studies indicate a changing trend in the C. difficile ribotype frequency distribution, 62 particularly the emergence of RT106 (also called Group "DH" or "NAP11") in regions 63 where it was previously rarely found. In 2008, RT106 was second to RT027 as the most 64 dominant ribotype in England, and was also identified in neighboring European countries 65 including . Howeve...

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Clostridium difficile Toxoid Vaccine Candidate Confers Broad Protection against a Range of Prevalent Circulating Strains in a Nonclinical Setting

Cited by 9 publications

References 49 publications

Structure of the cell-binding component of the Clostridium difficile binary toxin reveals a di-heptamer macromolecular assembly

Structure of the cell-binding component of the Clostridium difficile binary toxin reveals a di-heptamer macromolecular assembly

Phylogenomic analysis of Clostridioides difficile ribotype 106 strains reveals novel genetic islands and emergent phenotypes

Phylogenomic analysis ofClostridiodes difficileribotype 106 strains reveals novel genetic islands and emergent phenotypes

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