Virulence and genomic diversity among clinical isolates of ST1 (BI/NAP1/027) Clostridioides difficile

Dong, Qiwen; Lin, Huaiying; Allen, Marie-Maude; Garneau, Julian R.; Sia, Jonathan Kevin; Smith, Rita C.; Haro, Fidel; McMillen, Tracy; Pope, Rosemary L.; Metcalfe, Carolyn; Burgo, Victoria; Woodson, Che; Dylla, Nicholas P.; Kohout, Claire; Sundararajan, Anitha; Snitkin, Evan S.; Young, Vincent B.; Fortier, Louis‐Charles; Kamboj, Mini; Pamer, Eric G.

doi:10.1016/j.celrep.2023.112861

Cited by 7 publications

(23 citation statements)

References 79 publications

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“…Further, we confirmed a genetic relationship between cdtR and tcdB across C. difficile lineages that indicates some evolutionary pressure for maintaining the regulatory gene of the less prevalent toxin operon ( cdtR ). This phylogenomic analysis supports recent functional data from clade 2 isolates, where the presence of full-length cdtR increases the expression of tcdB and disease severity in an animal model of CDI 57 . While this was previously suggested in vitro , it is unclear how generalizable this relationship is across lineages 59 .…”

Section: Discussionsupporting

confidence: 87%

“…C. difficile isolates have an extensive pangenome, with genetic loci mobilized by conjugative elements and phages, and mobilizable elements playing a key role in C. difficile ’s lifecycle 57 . Temperate phages, which can undergo lytic replication or insert into the host genome as a latent prophage, are the only phages that have been isolated for C. difficile 58 .…”

Section: Resultsmentioning

confidence: 99%

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Genomic surveillance ofClostridioides difficiletransmission and virulence in a healthcare setting

Newcomer,

Fishbein,

Zhang

et al. 2023

Preprint

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Clostridioides difficileinfection (CDI) is a major cause of healthcare-associated diarrhea, despite the widespread implementation of contact precautions for patients with CDI. Here, we investigate strain contamination in a hospital setting and genomic determinants of disease outcomes. Across two wards over six months, we selectively culturedC. difficilefrom patients (n=384) and their environments. Whole-genome sequencing (WGS) of 146 isolates revealed that mostC. difficileisolates were from clade 1 (131/146, 89.7%), while only one isolate of the hypervirulent ST1 was recovered. Of culture-positive admissions, 17% of patients were diagnosed with CDI upon admission. We defined 29 strain networks at ≤ 2 core gene SNPs; 2 of these networks contain strains from different patients. Strain networks were temporally linked (p<0.0001). Across networks and over time, we found a minority of networks contained differences in phage populations. To understand genomic correlates of disease, we conducted WGS on an additional cohort ofC. difficile(n=102 isolates) from the same hospital and confirmed that clade 1 isolates are responsible for most CDI cases. We found that while toxigenicC. difficileisolates are associated with the presence ofcdtR, nontoxigenic isolates have an increased abundance of prophages. Our pangenomic analysis of clade 1 isolates suggests that while toxin genes (tcdABER and cdtR) were associated with CDI symptoms, they are dispensable for patient colonization. These data indicate toxigenic and nontoxigenicC. difficilecontamination persists in a hospital setting and highlight further investigation into how accessory genomic repertoires contribute toC. difficilecolonization and disease.

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Section: Discussionsupporting

confidence: 87%

Section: Resultsmentioning

confidence: 99%

Genomic surveillance ofClostridioides difficiletransmission and virulence in a healthcare setting

Newcomer,

Fishbein,

Zhang

et al. 2023

Preprint

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“…The four “representative” strains were all isolated from patients with C. difficile -associated disease and are frequently used as reference genomes for their clades and ribotype groups. Notably, RT027 (ST1), RT017 (ST45), and RT078 (ST11) strains are from ribotypes/ multilocus sequencing types that are frequently isolated from patients with C. difficile infection (CDI) (12, 19, 22, 25).…”

Section: Resultsmentioning

confidence: 99%

Unique growth and morphology properties of Clade 5Clostridioides difficilestrains revealed by single-cell time-lapse microscopy

Ribis,

Nieto-Acuña,

Dong

et al. 2024

Preprint

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Clostridioides difficileis a major One Health threat as an important gastrointestinal pathogen of both humans and agricultural animals. TheC. difficilespecies can be subdivided into 5 main clades, with Clade 5 currently undergoing speciation from Clades 1-4. Since Clade 5 strains are found more frequently in agricultural animals and can cause zoonotic infections, Clade 5 strains likely have evolved phenotypes that distinguish them from Clade 1-4 strains. Here, we compare the growth properties of Clade 5 strains to Clade 1, 2, and 4 strains using an anaerobic time-lapse microscopy system coupled with automated image analysis. These analyses revealed that Clade 5 strains grow faster than Clade 1, 2, and 4 strains and are more likely to form long chains of cells. Notably, the chaining phenotype was not shared among all Clade 5 strains examined, since 1 of the 9 strains did not form chains. Genomic analyses of the Clade 5 strains revealed that the orientation of thecmrswitch, an invertible DNA element controlling the expression of a signal transduction system that regulates chaining, correlates with the propensity of a given Clade 5 strain to form chains. Taken together, Clade 5 strains appear to have distinct growth properties that allow them to inhabit more diverse ecological niches.

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“…We previously characterized a ribotype 027 C. difficile isolate, ST1-75, that is avirulent in mouse models despite encoding all three toxins, including C. difficile ’s primary virulence factors Toxin A (TcdA), Toxin B (TcdB) and the binary toxin CDT. We showed that avirulence of ST1-75 is attributable to a natural mutation occurring in the cdtR gene, which encodes a response regulator for the binary toxin (27, 28). While CdtR regulates the expression of the gene encoding CDT, the natural in-frame deletion of 69 bp from the cdtR gene is sufficient to reduce the expression of not only the genes encoding CDT but also Toxin A and Toxin B (27, 29).…”

Section: Introductionmentioning

confidence: 99%

“…We showed that avirulence of ST1-75 is attributable to a natural mutation occurring in the cdtR gene, which encodes a response regulator for the binary toxin (27, 28). While CdtR regulates the expression of the gene encoding CDT, the natural in-frame deletion of 69 bp from the cdtR gene is sufficient to reduce the expression of not only the genes encoding CDT but also Toxin A and Toxin B (27, 29). Here, we found that coinfecting mice with the avirulent strain ST1-75 and the virulent strain R20291 prevents colitis induced by the virulent R20291 strain in mice and results in its rapid clearance from the gastrointestinal tract.…”

Section: Introductionmentioning

confidence: 99%

Protection againstClostridioides difficiledisease by a naturally avirulentC. difficilestrain

Dong,

Harper,

McSpadden

et al. 2024

Preprint

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Clostridioides difficile (C. difficile) strains belonging to the epidemic BI/NAP1/027 (RT027) group have been associated with increased transmissibility and disease severity. In addition to the major toxin A and toxin B virulence factors, RT027 strains also encode the CDT binary toxin. Our lab previously identified a toxigenic RT027 isolate, ST1-75, that is avirulent in mice despite densely colonizing the colon. Here, we show that co-infecting mice with the avirulent ST1-75 and virulent R20291 strains protects mice from colitis due to rapid clearance of the virulent strain and persistence of the avirulent strain. Although avirulence of ST1-75 is due to a mutation in the cdtR gene, which encodes a response regulator that modulates the production of all three C. difficile toxins, the ability of ST1-75 to protect against acute colitis is not directly attributable to the cdtR mutation. Metabolomic analyses indicate that the ST1-75 strain depletes amino acids more rapidly than the R20291 strain and supplementation with amino acids ablates ST1-75 s competitive advantage, suggesting that the ST1-75 strain limits the growth of virulent R20291 bacteria by amino acid depletion. Since the germination kinetics and sensitivity to the co-germinant glycine are similar for the ST1-75 and R20291 strains, our results identify the rapidity of in vivo nutrient depletion as a mechanism providing strain-specific, virulence-independent competitive advantages to different BI/NAP1/027 strains. They also suggest that the ST1-75 strain may, as a biotherapeutic agent, enhance resistance to CDI in high-risk patients.

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Virulence and genomic diversity among clinical isolates of ST1 (BI/NAP1/027) Clostridioides difficile

Cited by 7 publications

References 79 publications

Genomic surveillance ofClostridioides difficiletransmission and virulence in a healthcare setting

Genomic surveillance ofClostridioides difficiletransmission and virulence in a healthcare setting

Unique growth and morphology properties of Clade 5Clostridioides difficilestrains revealed by single-cell time-lapse microscopy

Protection againstClostridioides difficiledisease by a naturally avirulentC. difficilestrain

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