UC2 : One Health approach to the emergence, transition and dissemination of antimicrobial resistance in Acinetobacter baumannii

Image/photo illustrant le use case

Members

Coordinator : 

X. Charpentier, Inserm U1111/CIRI (Lyon), Bacteriology

Team members :          

M. Hugoni, UMR 5557/LEM (Villeurbanne), Bacterial ecology

L. Jacob, UMR 5558/LBBE (Villeurbanne), Statistics

S. Nazaret, UMR 5557/LEM (Villeurbanne), Bacterial ecology

E. Rocha, UMR 3525/GEM (Paris), Bacterial genome evolution

S. Venner, UMR 5558/LBBE (Villeurbanne), Ecology

C. Escobar, Inserm U1111/CIRI (Lyon), Bacteriology

Objective and outcome 

This use case aims to demonstrate the contribution of the ABRomics platform in the analysis of antimicrobial resistance in a One Health framework. Specifically, the project will require to store a large set of Acinetobacter baumannii (Ab) genomes sampled from different environments, along with their metadata and to perform a joint statistical and ecological analysis of these samples. 

Outcome: a blueprint describing the analysis of genomic and metagenomic data gathered over a gradient of anthropized environments to anticipate and control the spread of ABR in a One Health perspective.

Outline

Ab is a bacterium responsible for a wide range of severe hospital-acquired infections with a steadily increasing prevalence of multi-drug resistant strains throughout the world. The WHO has declared it as a priority pathogen for antimicrobial research efforts, a status reinforced by the recent discovery of hypervirulent strains. The identification in human and animal infections of strains from the same clonal group or carrying the same resistance genes, as well as recent discoveries of Ab from environmental sources (animal and terrestrial), call for an integrated “One Health” approach for this pathogen. Ab-one will develop 5 research axes to capture Ab populations (diversity/pangenome/resistome) on a global scale, to analyze their structure and eco-evolutionary dynamics, to identify AMR genes, to assess their intra- and inter-genomic movements, their association with virulence traits and finally, to develop mathematical models of the emergence, transmission and dissemination of AMR in Ab.

The One Health approach developed by this use case, based on a large data collection and analysis using extremely diverse and complementary expertise, could serve as a model for other emerging pathogens.

Scientific issues

The project will address the dynamics of AMR emergence, transmission and dissemination in Ab  from (and to) the natural, animal environments and clinical environments.

  1. Establishing the first global One Health network to capture the dynamics of Ab populations (diversity/pangenome/resistome) evolving in contrasting ecological conditions (from pristine to highly anthropized ecosystems, on a global scale (Europe, Caribbean Islands, Indian Ocean).
  2. Characterize the environmental microbial communities in which Ab evolves and identify associated selective pressures.
  3. Characterize the population structure of Ab (strain diversity within populations, variability between populations, between environments -natural environments, animals, humans)
  4. Identification of the AMR genes, their associations with mobile genetic elements and dynamics, horizontal gene transfer events
  5. Phenotypic characterization of the One Health collection of Ab isolates (antibiotic resistance levels, ability to acquire AMR genes)
  6. Exploit genomic and phenotypic data with association studies to explore the genetic basis of AMR. 
  7. Assess the relative importance of horizontal gene transfers (HGTs) and mobile genetic elements (MGEs) on the population dynamics of Ab and the emergence, transmission and dissemination of AMR.

Tasks for UC2 supported by WP1, WP2, WP3 and WP6

  1. Submission of metabarcoding sequencing data of longitudinal sampling of environmental microbial communities in which Ab resides, along with physico-chemical metadata of the environments.
  2. Processing of metabarcoding data to reveal the dynamics of the environmental microbial communities in which Ab evolves.
  3. Submission of large datasets of metadata and genome sequencing data (illumina and nanopore) of Ab isolates from 5 geographical areas (n=~3000).
  4. Assembly and uniform annotation of the Ab genomes. Detection of AMR genes, MGEs and recombination events. Analysis of gene flow in the species and closely related ones.
  5. Experimental determination of MIC levels to current and next generations of antibiotics (~25 antibiotics). Quantify the ability of the isolate to undergo HGT (2 distinct assays) and interact with the host (8 distinct assays)
  6. Conduct of gene-level and nucleotide-level genome-wide association studies to link AMR and virulence phenotypes to genotypes.
  7. Development of ecosystem models that encompass relevant phenomena from the molecular to the ecosystem scale.

Use case diagram

Interaction among the tasks of the Use Case Ab-One, the collected data and the expected outcome. The tasks will leverage the ABRomics platform ability to store and analyse data to produce a better understanding of AMR in Acinetobacter baumannii in a One Health framework.

Progresses & Ongoing work

Deliverable 1 : first One Health sample collection campaign

Deliverable 2 : longitudinal biotic and abiotic characteristics of the natural environments of Ab

Deliverable 3 : genome sequence and MIC profiles of ~3000 diverse isolates

Deliverable 4 : annotation of the genomes, construction of pan and core genomes

Deliverable 5 : population structure of the species and related bacteria

Deliverable 6 : analysis of the flux of genes within and between compartments

Deliverable 7 : identification of the putative genetic basis of antibiotic resistance and environmental association

Deliverable 8 : natural transformation and conjugation rates, barriers to HGT

Deliverable 9 : identification of MDR Ab strains with the potential to cause outbreaks

Deliverable 10 : new hypotheses regarding genotype-phenotype links

Deliverable 11 : construction of an integrated, multi-scale, modeling framework

Deliverable 12 : Modeling of the MGE-community and resistome dynamics