Re-emergence of Corynebacterium diphtheriae

Scheifer, Carole; Rolland‐Debord, Camille; Badell, Edgar; Reibel, Florence; Aubry, Alexandra; Pérignon, Alice; Patey, O.; Brisse, Sylvain; Caumes, Eric

doi:10.1016/j.medmal.2018.12.001

Cited by 16 publications

(13 citation statements)

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“…Even so, thousands of cases of diphtheria are still reported annually [15], and large outbreaks can quickly follow the disruption of public health systems [14,[16][17][18]. In countries with high vaccination coverage, diphtheria cases are associated with travel and migration from endemic regions [19][20][21]. As diphtheria vaccination is performed using an inactivated form of diphtheria toxin, it is not considered to prevent asymptomatic colonization and silent transmission of the pathogen, which still circulates and is the object of intense epidemiological surveillance [4].…”

Section: Introductionmentioning

confidence: 99%

Population genomics and antimicrobial resistance in Corynebacterium diphtheriae

et al. 2020

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Background Corynebacterium diphtheriae, the agent of diphtheria, is a genetically diverse bacterial species. Although antimicrobial resistance has emerged against several drugs including first-line penicillin, the genomic determinants and population dynamics of resistance are largely unknown for this neglected human pathogen. Methods Here, we analyzed the associations of antimicrobial susceptibility phenotypes, diphtheria toxin production, and genomic features in C. diphtheriae. We used 247 strains collected over several decades in multiple world regions, including the 163 clinical isolates collected prospectively from 2008 to 2017 in France mainland and overseas territories. Results Phylogenetic analysis revealed multiple deep-branching sublineages, grouped into a Mitis lineage strongly associated with diphtheria toxin production and a largely toxin gene-negative Gravis lineage with few toxin-producing isolates including the 1990s ex-Soviet Union outbreak strain. The distribution of susceptibility phenotypes allowed proposing ecological cutoffs for most of the 19 agents tested, thereby defining acquired antimicrobial resistance. Penicillin resistance was found in 17.2% of prospective isolates. Seventeen (10.4%) prospective isolates were multidrug-resistant (≥ 3 antimicrobial categories), including four isolates resistant to penicillin and macrolides. Homologous recombination was frequent (r/m = 5), and horizontal gene transfer contributed to the emergence of antimicrobial resistance in multiple sublineages. Genome-wide association mapping uncovered genetic factors of resistance, including an accessory penicillin-binding protein (PBP2m) located in diverse genomic contexts. Gene pbp2m is widespread in other Corynebacterium species, and its expression in C. glutamicum demonstrated its effect against several beta-lactams. A novel 73-kb C. diphtheriae multiresistance plasmid was discovered. Conclusions This work uncovers the dynamics of antimicrobial resistance in C. diphtheriae in the context of phylogenetic structure, biovar, and diphtheria toxin production and provides a blueprint to analyze re-emerging diphtheria.

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Section: Introductionmentioning

confidence: 99%

Population genomics and antimicrobial resistance in Corynebacterium diphtheriae

et al. 2020

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“…In Europe, 139 cases were reported between 2014 and 2018, a majority of which followed introduction of C. diphtheriae from endemic regions [4]. In these settings, transmission is rare and only small clusters of patients or carriers are observed [5,6]. Differently, in settings where public health action is disrupted and vaccination coverage has decreased, several large outbreaks of diphtheria in its typical clinical form have occurred in recent years [7][8][9].…”

Section: Introductionmentioning

confidence: 99%

Genomic Epidemiology and Strain Taxonomy of Corynebacterium diphtheriae

et al. 2021

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Background Corynebacterium diphtheriae is highly transmissible and can cause large diphtheria outbreaks where vaccination coverage is insufficient. Sporadic cases or small clusters are observed in high-vaccination settings. The phylogeography and short timescale evolution of C. diphtheriae are not well understood, in part due to a lack of harmonized analytical approaches of genomic surveillance and strain tracking. Methods We combined 1,305 genes with highly reproducible allele calls into a core genome multilocus sequence typing (cgMLST) scheme. We analyzed cgMLST genes diversity among 602 isolates from sporadic clinical cases, small clusters or large outbreaks. We defined sublineages based on the phylogenetic structure within C. diphtheriae and strains based on the highest number of cgMLST mismatches within documented outbreaks. We performed time-scaled phylogenetic analyses of major sublineages. Results The cgMLST scheme showed high allele call rate in C. diphtheriae and the closely related species C. belfantii and C. rouxii . We demonstrate its utility to delineate epidemiological case clusters and outbreaks using a 25 mismatches threshold, and reveal a number of cryptic transmission chains, most of which are geographically restricted to one or a few adjacent countries. Subcultures of the vaccine strain PW8 differed by up to 20 cgMLST mismatches. Phylogenetic analyses revealed short timescale evolutionary gain or loss of the diphtheria toxin and biovar-associated genes. We devised a genomic taxonomy of strains and deeper sublineages (defined using a 500 cgMLST mismatches threshold), currently comprising 151 sublineages, only a few of which are geographically widespread based on current sampling. The cgMLST genotyping tool and nomenclature was made publicly accessible at https://bigsdb.pasteur.fr/diphtheria . Conclusions Standardized genome-scale strain genotyping will help tracing transmission and geographic spread of C. diphtheriae . The unified genomic taxonomy of C. diphtheriae strains provides a common language for studies into the ecology, evolution and virulence heterogeneity among C. diphtheriae sublineages.

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Section: Introductionmentioning

confidence: 99%

Genomic epidemiology and strain taxonomy ofCorynebacterium diphtheriae

Guglielmini

Hennart

Badell

et al. 2021

Preprint

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Background: Corynebacterium diphtheriae is highly transmissible and can cause large diphtheria outbreaks where vaccination coverage is insufficient. Sporadic cases or small clusters are observed in high-vaccination settings. The phylogeography and short timescale evolution of C. diphtheriae are not well understood, in part due to a lack of harmonized analytical approaches of genomic surveillance and strain tracking. Methods: >We combined 1,305 genes with highly reproducible allele calls into a core genome multilocus sequence typing (cgMLST) scheme. We analyzed cgMLST genes diversity among 602 isolates from sporadic clinical cases, small clusters or large outbreaks. We defined sublineages based on the phylogenetic structure within C. diphtheriae and strains based on the highest number of cgMLST mismatches within documented outbreaks. We performed time-scaled phylogenetic analyses of major sublineages. Results: The cgMLST scheme showed high allele call rate in C. diphtheriae and the closely related species C. belfantii and C. rouxii. We demonstrate its utility to delineate epidemiological case clusters and outbreaks using a 25 mismatches threshold, and reveal a number of cryptic transmission chains, most of which are geographically restricted to one or a few adjacent countries. Subcultures of the vaccine strain PW8 differed by up to 20 cgMLST mismatches. Phylogenetic analyses revealed short timescale evolutionary gain or loss of the diphtheria toxin and biovar-associated genes. We devised a genomic taxonomy of strains and deeper sublineages (defined using a 500 cgMLST mismatches threshold), currently comprising 151 sublineages, only a few of which are geographically widespread based on current sampling. The cgMLST genotyping tool and nomenclature was made publicly accessible at https://bigsdb.pasteur.fr/diphtheria. Conclusions: Standardized genome-scale strain genotyping will help tracing transmission and geographic spread of C. diphtheriae. The unified genomic taxonomy of C. diphtheriae strains provides a common language for studies into the ecology, evolution and virulence heterogeneity among C. diphtheriae sublineages.

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Re-emergence of Corynebacterium diphtheriae

Cited by 16 publications

References 10 publications

Population genomics and antimicrobial resistance in Corynebacterium diphtheriae

Population genomics and antimicrobial resistance in Corynebacterium diphtheriae

Genomic Epidemiology and Strain Taxonomy of Corynebacterium diphtheriae

Genomic epidemiology and strain taxonomy ofCorynebacterium diphtheriae

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