NIH Research Festival
Bordetella hinzii is a genetic relative of B. pertussis that typically infects the respiratory tracts of birds. Zoonotic transmission of B. hinzii to immunocompromised humans has been demonstrated. Here we describe extensive adaptive evolution of B. hinzii in a patient with recessive germline IL-12Rβ1 deficiency who presented with chronic bloodstream and gastrointestinal tract infection. Twenty-two B. hinzii isolates were cultured over 16 months from blood and stool and demonstrated a striking range of colonial morphologies and antimicrobial susceptibilities. To elucidate the genomic basis of the observed phenotypic diversity, isolates were sequenced using Illumina and PacBio technologies. Comparative analyses demonstrated that all isolates were clonal, but had undergone extensive genomic diversification. Comparison to a computationally-derived ancestral genome allowed estimation that 19 of 22 isolates had 42 - 584 mutations (median: 375) since introduction into the host. Interestingly, three isolates differed by > 1000 substitutions from the constructed ancestor. Analysis demonstrated mutations in the mutM and mutY genes in these isolates, and mutational signatures were consistent with hypermutator phenotypes. Strikingly, we found that some genes were repeatedly mutated in the course of host adaptation, including the osmoregulatory sensor protein EnvZ and the two-component system bvgA/S regulating virulence in Bordetella. The extensive genomic divergence and repeated independent mutations of the same genes between isolates suggests rapid and focused evolutionary adaptation to the human host following the jump from an animal reservoir. Study of established zoonotic infections in the immunocompromised host may yield novel insights into the immunobiology of pathogen host-jumps and intra-host evolution.
Scientific Focus Area: Microbiology and Infectious Diseases
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