Year: 2022
Type: article
Abstract: The medical and scientific response to emerging and established pathogens is often severely hampered by ignorance of the genetic determinants of virulence, drug resistance and clinical outcomes that could be used to identify therapeutic drug targets and forecast patient trajectories. Taking the newly emergent multidrug-resistant bacteria Mycobacterium abscessus as an example, we show that combining high-dimensional phenotyping with whole-genome sequencing in a phenogenomic analysis can rapidly reveal actionable systems-level insights into bacterial pathobiology. Through phenotyping of 331 clinical isolates, we discovered three distinct clusters of isolates, each with different virulence traits and associated with a different clinical outcome. We combined genome-wide association studies with proteome-wide computational structural modelling to define likely causal variants, and employed direct coupling analysis to identify co-evolving, and therefore potentially epistatic, gene networks. We then used in vivo CRISPR-based silencing to validate our findings and discover clinically relevant M. abscessus virulence factors including a secretion system, thus illustrating how phenogenomics can reveal critical pathways within emerging pathogenic bacteria.
Source: Nature Microbiology
Institutions: MRC Laboratory of Molecular Biology, University of Basel, University of Cambridge, Wellcome Sanger Institute, Molecular Immunity Unit, Cambridge Centre for AI in Medicine, Imperial College London, Science and Technology Facilities Council, University of Freiburg, Royal Papworth Hospital, Papworth Hospital NHS Foundation Trust
Language: English
Subfield: Epidemiology
Field: Medicine
Domain: Health Sciences
Open Access status: hybrid
Estimated APC paid: $11,390
Funders: National Science Foundation, European Molecular Biology Organization, European Respiratory Society, Wellcome Trust, National Institute for Health and Care Research, Cystic Fibrosis Trust, Rosetrees Trust, Lloyd's Tercentenary Research Foundation, Deutsche Forschungsgemeinschaft, Schweizerischer Nationalfonds zur Förderung der Wissenschaftlichen Forschung, Fondation Botnar, Helmut Horten Stiftung, Medical Research Council, NIHR Cambridge Biomedical Research Centre
Awards: G1210355066, The host response to Staphylococcus aureus infection., G1827369112, Molecular basis of Mycobacterium Abscessus heterogeneity during stress, G4146039213, Innate immune regulation of infection tolerance, The host response to Staphylococcus aureus infection., G5163037823, The host response to Staphylococcus aureus infection., Mycobacterium abscessus adaptation to host and anti-mycobacterial drugs, G6868616705, Mechanistic studies of the reactions of peroxynitrite and nitrogen monoxide with heme proteins, G8297804747, Revenus accessoires tirés de l'agriculture et situation des exploitations agricoles petites et moyennes., G8429191467, Identification, characterization and targeting of efflux pumps in Mycobacterium abscessus, G8553597505, Wellcome Trust Sanger Institute - generic account for deposition of all core- funded research papers
OpenAlex ID: W4293237624