The genus Yersinia has been used as a model system to study pathogen evolution. Using whole-genome sequencing of all Yersinia species, we delineate the gene complement of the whole genus and define patterns of virulence evolution. Multiple distinct ecological specializations appear to have split pathogenic strains from environmental, nonpathogenic lineages. This split demonstrates that contrary to hypotheses that all pathogenic Yersinia species share a recent common pathogenic ancestor, they have evolved independently but followed parallel evolutionary paths in acquiring the same virulence determinants as well as becoming progressively more limited metabolically. Shared virulence determinants are limited to the virulence plasmid pYV and the attachment invasion locus ail. These acquisitions, together with genomic variations in metabolic pathways, have resulted in the parallel emergence of related pathogens displaying an increasingly specialized lifestyle with a spectrum of virulence potential, an emerging theme in the evolution of other important human pathogens.genomics metabolic streamlining | pathoadaptation | Enterobacteriaceae B acterial species are defined on the basis of phenotypic characteristics, such as cellular morphology and biochemical characteristics, as well as DNA-DNA hybridization and 16S rRNA comparison. Using high-throughput whole-genome approaches we can now move beyond classic methods and develop population frameworks to reconstruct accurate inter-and intraspecies relationships and gain insights into the complex patterns of gene flux that define different taxonomic groups.Bacterial whole-genome sequencing has revealed enormous heterogeneity in gene content, even between members of the same species. From a bacterial perspective the acquisition of new genes provides the flexibility to adapt and exploit novel niches and opportunities. From a human perspective, integration of genes by bacteria has been directly linked to the emergence of new pathogenic clones, often from formerly harmless lineages (1, 2). In addition to gene gain, gene loss is also strongly associated with host restriction in acutely pathogenic bacterial species, such as Yersinia pestis and Salmonella enterica serovars, including Salmonella Typhi (3-5), where gene loss can remove functions unnecessary in the new niche (6). These specialist pathogens show a much higher frequency of functional gene loss than closely related host generalist pathogens, such as Yersinia pseudotuberculosis (7).Previous Yersinia genome studies (8, 9) have examined the evolution of pathogenicity by comparing strains from a selection of species or species subtypes within the genus, limiting our understanding of the evolutionary context of individual species. The majority of the Yersinia species are found in the environment and do not cause disease in mammals. Three species are known as human pathogens: the plague bacillus Y. pestis and the enteropathogens Yersinia enterocolitica and Y. pseudotuberculosis. SignificanceOur past understanding of pathogen evo...

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Plague is a vector-borne disease caused by Yersinia pestis. Transmitted by fleas from rodent reservoirs, Y. pestis emerged <6000 years ago from an enteric bacterial ancestor through events of gene gain and genome reduction. It is a highly remarkable model for the understanding of pathogenic bacteria evolution, and a major concern for public health as highlighted by recent human outbreaks. A complex set of virulence determinants, including the Yersinia outer-membrane proteins (Yops), the broad-range protease Pla, pathogen-associated molecular patterns (PAMPs), and iron capture systems play critical roles in the molecular strategies that Y. pestis employs to subvert the human immune system, allowing unrestricted bacterial replication in lymph nodes (bubonic plague) and in lungs (pneumonic plague). Some of these immunogenic proteins as well as the capsular antigen F1 are exploited for diagnostic purposes, which are critical in the context of the rapid onset of death in the absence of antibiotic treatment (less than a week for bubonic plague and <48 h for pneumonic plague). Here, we review recent research advances on Y. pestis evolution, virulence factor function, bacterial strategies to subvert mammalian innate immune responses, vaccination, and problems associated with pneumonic plague diagnosis.

The genus Yersinia comprises species that differ widely in their pathogenic potential and public-health significance. Yersinia pestis is responsible for plague, while Yersinia enterocolitica is a prominent enteropathogen. Strains within some species, including Y. enterocolitica, also vary in their pathogenic properties. Phenotypic identification of Yersinia species is time-consuming, labour-intensive and may lead to incorrect identifications. Here, we developed a method to automatically identify and subtype all Yersinia isolates from their genomic sequence. A phylogenetic analysis of Yersinia isolates based on a core subset of 500 shared genes clearly demarcated all existing Yersinia species and uncovered novel, yet undefined Yersinia taxa. An automated taxonomic assignment procedure was developed using species-specific thresholds based on core-genome multilocus sequence typing (cgMLST). The performance of this method was assessed on 1843 isolates prospectively collected by the French National Surveillance System and analysed in parallel using phenotypic reference methods, leading to nearly complete (1814; 98.4 %) agreement at species and infra-specific (biotype and serotype) levels. For 29 isolates, incorrect phenotypic assignments resulted from atypical biochemical characteristics or lack of phenotypic resolution. To provide an identification tool, a database of cgMLST profiles and reference taxonomic information has been made publicly accessible (https://bigsdb.pasteur.fr/yersinia). Genomic sequencing-based identification and subtyping of any Yersinia is a powerful and reliable novel approach to define the pathogenic potential of isolates of this medically important genus.

The frequency of human infection caused by certain Yersinia subgroups might be related to the frequency of exposure to specific animal sources. In contrast, non-pathogenic Yersinia were commonly isolated from foodstuffs and the environment, most probably accounting for the abundance of non-pathogenic Yersinia recovered from human stools.

hThe genus Yersinia is a large and diverse bacterial genus consisting of human-pathogenic species, a fish-pathogenic species, and a large number of environmental species. Recently, the phylogenetic and population structure of the entire genus was elucidated through the genome sequence data of 241 strains encompassing every known species in the genus. Here we report the mining of this enormous data set to create a multilocus sequence typing-based scheme that can identify Yersinia strains to the species level to a level of resolution equal to that for whole-genome sequencing. Our assay is designed to be able to accurately subtype the important human-pathogenic species Yersinia enterocolitica to whole-genome resolution levels. We also report the validation of the scheme on 386 strains from reference laboratory collections across Europe. We propose that the scheme is an important molecular typing system to allow accurate and reproducible identification of Yersinia isolates to the species level, a process often inconsistent in nonspecialist laboratories. Additionally, our assay is the most phylogenetically informative typing scheme available for Y. enterocolitica. The Gram-negative Yersinia is one of the most important and well-studied bacterial genera, consisting of three human pathogens. Y. pestis is the causative agent of bubonic and pneumonic plague and is a recently diverged clone of Yersinia pseudotuberculosis (1), which alongside Y. enterocolitica is a zoonotic gastrointestinal pathogen (2). The remaining species are not associated with human disease and are considered to be environmental organisms, with the exception of the common fish pathogen Y. ruckeri (2) and the insecticidal species Y. entomophaga. Of the human-pathogenic species, Y. enterocolitica is the most common etiological agent of human disease, and in Germany and Scandinavia, the numbers of cases of human intestinal yersiniosis caused by Y. enterocolitica rival those caused by Salmonella (3). Y. enterocolitica is in itself a very diverse species that is classically subdivided into nonpathogenic, low-pathogenic, and high-pathogenic biotypes based on virulence in a mouse infection model (4). Biotype 1A isolates are considered nonpathogenic, which is concordant with a lack of the major Y. enterocolitica virulence factors such as pYV, invasin, YadA, and Ail (5), although there are numerous reports of biotype 1A human carriage (6, 7). Biotype 1B isolates are high pathogenic, which is concordant with carriage of the high-pathogenicity island, but isolation from human disease cases is very rare with the exception of notable outbreaks such as the recent emergence in Poland (8). Biotype 2 to 4 isolates are low pathogenic and are globally the most common causes of human gastrointestinal yersiniosis (4). Biotype 5 isolates are also considered low pathogenic but have only been isolated from wild hare populations and are very rare in nature (5).From a clinical perspective, the isolation and subsequent identification of Yersinia and in particular Y. enterocoli...

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Identifying key reservoirs for zoonoses is crucial for understanding variation in incidence. Plague re-emerged in Mahajanga, Madagascar in the 1990s but there has been no confirmed case since 1999. Here we combine ecological and genetic data, from during and after the epidemics, with experimental infections to examine the role of the shrew Suncus murinus in the plague epidemiological cycle. The predominance of S. murinus captures during the epidemics, their carriage of the flea vector and their infection with Yersinia pestis suggest they played an important role in the maintenance and transmission of plague. S. murinus exhibit a high but variable resistance to experimental Y. pestis infections, providing evidence of its ability to act as a maintenance host. Genetic analyses of the strains isolated from various hosts were consistent with two partially-linked transmission cycles, with plague persisting within the S. murinus population, occasionally spilling over into the rat and human populations. The recent isolation from a rat in Mahajanga of a Y. pestis strain genetically close to shrew strains obtained during the epidemics reinforces this hypothesis and suggests circulation of plague continues. The observed decline in S. murinus and Xenopsylla cheopis since the epidemics appears to have decreased the frequency of spillover events to the more susceptible rats, which act as a source of infection for humans. Although this may explain the lack of confirmed human cases in recent years, the current circulation of plague within the city highlights the continuing health threat.