Mycobacterium abscessus pathogenesis identified by phenogenomic analyses

Mycobacterium abscessus pathogenesis identified by phenogenomic analyses

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 newl...

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Bibliographic Details
Published in:Nature microbiology 2022-09, Vol.7 (9), p.1431-1441
Main Authors: Boeck, Lucas, Burbaud, Sophie, Skwark, Marcin, Pearson, Will H, Sangen, Jasper, Wuest, Andreas W, Marshall, Eleanor K P, Weimann, Aaron, Everall, Isobel, Bryant, Josephine M, Malhotra, Sony, Bannerman, Bridget P, Kierdorf, Katrin, Blundell, Tom L, Dionne, Marc S, Parkhill, Julian, Andres Floto, R
Format: Article
Language:eng
Subjects:
Antibiotic resistance
Clinical isolates
Computer applications
CRISPR
Drug resistance
Epistasis
Gene mapping
Genome, Bacterial
Genome-wide association studies
Genome-Wide Association Study
Genomes
Humans
Multidrug resistance
Mycobacterium abscessus
Mycobacterium Infections, Nontuberculous
Phenotyping
Proteomes
Therapeutic targets
Virulence
Virulence Factors
Whole genome sequencing
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Summary: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.
ISSN:2058-5276
2058-5276