Genomic Epidemiology and Microevolution of the Zoonotic PathogenCorynebacterium ulcerans

Abstract

AbstractCorynebacterium ulceransis an emerging zoonotic pathogen that belongs to theCorynebacterium diphtheriae(Cd) species complex (CdSC), and that causes diphtheria-like infections in humans. Our understanding of the transmission, phylogeography and evolution ofC. ulceransremains limited, in part due to the lack of a standardized genomic epidemiology toolkit.The aim of this work was to develop a core genome multi-locus sequence typing (cgMLST) scheme for high-resolution genotyping and classification ofC. ulceransstrains, and to explore transmission, spatial spread and genomic evolution among 582C. ulceransisolates from sporadic clinical cases and reported case clusters.The cgMLST scheme combines 1,628 loci with highly reproducible allele calls and shows high strain subtyping resolution. We demonstrate its utility for capturing population structure by defining sublineages (SL, maximum 940 allele differences) and clonal groups (CG, 194 allele differences, AD) and for epidemiological surveillance by defining genetic clusters, i.e., previously undetected chains of transmission (25 AD). Genetic clusters correspond to cryptic and case clusters that were associated with specific geographical regions within France. MajorC. ulceranssublineages (SL325, SL331, SL339) and clonal groups (CG325, CG331, CG583) showed strong associations with diphtheria toxin variants and tox-carrying prophages or other genetic elements. The evolutionary dynamics oftoxgene presence or absence varied sharply among clonal groups. The cgMLST scheme is publicly available (https://bigsdb.pasteur.fr/diphtheria) and provides a common framework for investigating the ecology, evolution and variations in virulence amongC. ulceransstrains. The implementation of a standardized high-resolution genotyping method will also facilitate the tracing ofC. ulceranstransmission and spread across hosts and from local to global spatial scales.