A global *Corynebacterium diphtheriae* genomic framework sheds light on current diphtheria reemergenceuse asterix (*) to get italics

Melanie Hennart, Chiara Crestani, Sebastien Bridel, Nathalie Armatys, Sylvie Brémont, Annick Carmi-Leroy, Annie Landier, Virginie Passet, Laure Fonteneau, Sophie Vaux, Julie Toubiana, Edgar Badell, Sylvain BrissePlease use the format "First name initials family name" as in "Marie S. Curie, Niels H. D. Bohr, Albert Einstein, John R. R. Tolkien, Donna T. Strickland"

2023

<p style="text-align: justify;"><strong>Background</strong></p> <p style="text-align: justify;">Diphtheria, caused by <em>Corynebacterium diphtheriae</em>, reemerges in Europe since 2022. Genomic sequencing can inform on transmission routes and genotypes of concern, but currently, no standard approach exists to detect clinically important genomic features and to interpret emergence in the global <em>C. diphtheriae</em> population framework.</p> <p style="text-align: justify;"><strong>Methods</strong></p> <p style="text-align: justify;">We developed the bioinformatics pipeline diphtOscan (available at <a href="https://gitlab.pasteur.fr/BEBP/diphtoscan" target="_blank" rel="noopener">https://gitlab.pasteur.fr/BEBP/diphtoscan</a>) to extract from genomes of Corynebacteria of the diphtheriae species complex, medically relevant features including toxgene presence and disruption. We analyzed 101 human <em>C. diphtheriae</em> isolates collected in 2022 in metropolitan and overseas France (France-2022). To define the population background of this emergence, we sequenced 379 additional isolates (mainly from France, 2018-2021) and collated 870 publicly-available genomes.</p> <p style="text-align: justify;"><strong>Results</strong></p> <p style="text-align: justify;">The France-2022 isolates comprised 45 tox-positive (44 toxigenic) isolates, mostly imported, belonging to 10 sublineages (&lt;500 distinct core genes). The global dataset comprised 245 sublineages and 33.9% tox-positive genomes, with diphtOscan predicting non-toxigenicity in 16.0% of these. 12% of the global isolates, and 43.6% of France-2022 ones, were multidrug resistant. Convergence of toxigenicity with penicillin and erythromycin resistance was observed in 2 isolates from France-2022. Phylogenetic lineages Gravis and Mitis contrasted strikingly in their pathogenicity-associated genes.</p> <p style="text-align: justify;"><strong>Conclusions</strong></p> <p style="text-align: justify;">This work provides a bioinformatics tool and global population framework to analyze <em>C. diphtheriae</em> genomes, revealing important heterogeneities in virulence and resistance features. Emerging genotypes combining toxigenicity and first-line antimicrobial resistance represent novel threats. Genomic epidemiology studies of <em>C. diphtheriae</em> should be intensified globally to improve understanding of reemergence and spatial spread.</p>

https://www.ncbi.nlm.nih.gov/bioproject/413678You should fill this box only if you chose 'All or part of the results presented in this preprint are based on data'. URL must start with http:// or https://

https://gitlab.pasteur.fr/BEBP/diphtoscan, https://doi.org/10.5281/zenodo.7774709You should fill this box only if you chose 'Scripts were used to obtain or analyze the results'. URL must start with http:// or https://

diphtheria, genomic sequencing, antimicrobial resistance, virulence, epidemiology, transmission, 2022 reemergence, bioinformatics tool

NonePlease indicate the methods that may require specialised expertise during the peer review process (use a comma to separate various required expertises).

Drug resistance, tolerance and persistence, Epidemiology, Evolution of hosts, infectious agents, or vectors, Genomics, functional genomics of hosts, infectious agents, or vectors, Microbiology of infections, Population genetics of hosts, infectious agents, or vectors

Michael Weigand yrh8@cdc.gov Pertussis and Diphtheria Laboratory, CDC, Atlanta, Andreas Sing National Consiliary Laboratory for Diphtheria, Oberschleißheim, Germany andreas.sing@lgl.bayern.de, Marc Romney St. Paul's Hospital and Providence Health Care, Vancouver mromney@providencehealth.bc.ca, Paul Hoskisson paul.hoskisson@strath.ac.uk Strathclyde U, Glasgow, UK, Renato Orsi Cornell Univesity rho2@cornell.edu, Stephen Bentley Wellcome Trust Sanger Institute sdb@sanger.ac.uk, Andreas Tauch Center for Biotechnology (CeBiTec), Bielefeld University, Bielefeld, Germany tauch@cebitec.uni-bielefeld.de, Ankur Mutreja Cambridge University am872@cam.ac.u, Alexandra Zasada National Institute of Hygiene Warsaw, Poland azasada@pzh.gov.pl, Andreas Burkovski Friedrich-Alexander-University, Erlangen, Germany andreas.burkovski@fau.de

e.g. John Doe john@doe.com

No need for them to be recommenders of PCIInfections. Please do not suggest reviewers for whom there might be a conflict of interest. Reviewers are not allowed to review preprints written by close colleagues (with whom they have published in the last four years, with whom they have received joint funding in the last four years, or with whom they are currently writing a manuscript, or submitting a grant proposal), or by family members, friends, or anyone for whom bias might affect the nature of the review - see the code of conduct

2023-03-09 16:02:27

Rodolfo García-Contreras

Ankur Mutreja