Plague is a disease that has severely impacted the history of humankind during the course of three pandemics, killing millions of human beings. Nearly 50,000 human plague cases have been reported to the World Health Organization (WHO) by 26 countries during the last thirty years, and a significant increase observed during this period justifies the inclusion of this disease in the ‘re-emergent diseases’ list. The plague etiologic agent, the Gram-negative bacterium Yersinia pestis, is also included among those microorganisms that can be potentially used as a biological weapon: indeed, Y. pestis is one of the most pathogenic agents in the bacterial world. However, the genetic bases of the molecular virulence mechanisms specific to Y. pestis have not been thoroughly characterized. Moreover, antibiotic resistant strains have been sporadically discovered, but we ignore the historical trend behind the acquisition and the diffusion risk of these resistances, as well as the diversity of the resistance repertoire present in diverse populations of Y. pestis. Finally, despite previous studies designed to understand the biodiversity of Y. pestis, nowadays there are no cartography representations of the genetic diversity of the plague agent based on the study of many genomes isolated in all the endemic regions for the disease in the world. In the CARTO-PEST project, we propose to benefit of recent significant technological improvements in the field of genomic in order to sequence and analyze the genomes of Y. pestis strains isolated in different regions of the world. At first, we will take advantage of the analysis of a unique Y. pestis strain collection, patrimony of the Yersinia Research Unit (Institut Pasteur) that harbors around 2,000 strains isolated along the XXth and XXIst centuries from diverse geographic origins, including all the endemic regions for the disease in the world. Our genomic database will be completed with Y. pestis sequencing genomic data from public repositories. We also envision collaborations with foreign laboratories in the plague endemic regions (Americas: United States, Peru; Asia: China, India; Africa: Congo Democratic Republic, Madagascar) in order to import new Y. pestis strains or to collect genomic data from sequencing performed in the foreign collaborating laboratories. Then, our research program proposes therefore the following steps: a) to characterize the genetic diversity and the genomic structure of the species Y. pestis; b) to identify/associate specific markers from a define geographic region (cartography); c) to identify antibiotic resistance factors and to evaluate their acquisition and dissemination risk according to the resistance mechanism (transmissible or not); d) to evaluate the genetic proximity of strains isolated during epidemics compared to non-epidemic endemic strains; e) to evaluate the virulence of the different clonal complexes identified in a) and d) in experimental mouse infection models; and f) to identify and characterize putative novel virulence factors. The CARTO-PEST project will allow to improve our knowledge of the biodiversity of the plague agent, to identify specific markers of geographic origin, to study the presence of antibiotic resistance factors and evaluate their dissemination risk, to establish a cartography of the genetic diversity of Y. pestis strains isolated from all over the world (and in particular in plague endemic zones), and to better understand the virulence of the plague agent by characterizing putative novel virulence factors identified through correlation of epidemiological and genomic data, studied in vivo and potentially contributing to the improvement of vaccine candidates.
Monsieur Javier PIZARRO-CERDA (INSTITUT PASTEUR)
The author of this summary is the project coordinator, who is responsible for the content of this summary. The ANR declines any responsibility as for its contents.
IP INSTITUT PASTEUR
Help of the ANR 296,298 euros
Beginning and duration of the scientific project: December 2018 - 36 Months