Metabolic adaptation of Bordetella hinzii in an immunocompromised host

Authors

• SJ Baek
• L Wang
• E Arda

Abstract

Bordetella hinzii is an emerging zoonotic pathogen. We recently characterized a series of B. hinzii isolates collected from the bloodstream and gastrointestinal tract of an IL12-RB1-deficient patient over 45 months. Genomic analysis revealed isolates derived from a clonal lineage that underwent extensive within-host diversification. Notably, 20/24 isolates shared a substitution in DNA polymerase III (DnaQ E9G) conferring a DNA proofreading defect resulting in hypermutation, potentially accelerating within-host adaptive evolution. In this work, we study genomic and phenotypic features of metabolic reprogramming that occurred during host adaptation. Using phenotypic microarrays, we assessed the capacity of each isolate to metabolize hundreds of substrates. Hierarchical clustering analysis grouped isolates into two clusters based on utilization of nitrogen sources, with one cluster demonstrating significantly greater utilization of 173/368 nitrogen sources (Bonferroni-corrected p<0.05). To investigate specific metabolic alterations, the four DnaQ wildtype isolates were cultured in defined Stainer-Scholte media. Interestingly, only one isolate demonstrated growth. Comparative genomics analysis revealed that growth-impaired isolates had mutations in metE encoding a methionine synthase, or pheA encoding a chorismate mutase/prephenate dehydratase involved in phenylalanine biosynthesis. Supplementation with L-Met or L-Phe, respectively, rescued growth in a concentration-dependent manner. Our work demonstrates the evolution of specific auxotrophies in these isolates during the course of infection. Future work will involve 1) complementation of wildtype genes into isolates to validate the genetic basis of these auxotrophies, and 2) competition assays to understand the fitness consequences of these mutations, which occurred in isolates that rose to dominance at defined times in the infection course.

Scientific Focus Area: Microbiology and Infectious Diseases

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