RESUMO
Zoonotic transfer of animal pathogens to human hosts can generate novel agents, but the genetic events following such host jumps are not well studied. Here we characterize the mechanisms driving adaptive evolution of the emerging zoonotic pathogen Bordetella hinzii in a patient with interleukin-12 receptor ß1 deficiency. Genomic sequencing of 24 B. hinzii isolates cultured from blood and stool over 45 months revealed a clonal lineage that had undergone extensive within-host genetic and phenotypic diversification. Twenty of 24 isolates shared an E9G substitution in the DNA polymerase III ε-subunit active site, resulting in a proofreading deficiency. Within this proofreading-deficient clade, multiple lineages with mutations in DNA repair genes and altered mutational spectra emerged and dominated clinical cultures for more than 12 months. Multiple enzymes of the tricarboxylic acid cycle and gluconeogenesis pathways were repeatedly mutated, suggesting rapid metabolic adaptation to the human environment. Furthermore, an excess of G:C > T:A transversions suggested that oxidative stress shaped genetic diversification during adaptation. We propose that inactivation of DNA proofreading activity in combination with prolonged, but sub-lethal, oxidative attack resulting from the underlying host immunodeficiency facilitated rapid genomic adaptation. These findings suggest a fundamental role for host immune phenotype in shaping pathogen evolution following zoonotic infection.
Assuntos
Adaptação Fisiológica/genética , Bordetella/genética , Evolução Molecular , Hospedeiro Imunocomprometido/genética , Animais , Proteínas de Bactérias/genética , Zoonoses Bacterianas/microbiologia , Bordetella/classificação , Bordetella/fisiologia , DNA Polimerase III/genética , Interações Hospedeiro-Patógeno/genética , Humanos , Mutação , Filogenia , Aves Domésticas/microbiologia , Receptores de Interleucina-12/deficiência , Receptores de Interleucina-12/genéticaRESUMO
The long-term use of left ventricular assist devices (LVADs) is becoming more common among the end-stage heart failure population. At the time of heart transplantation, most of the LVAD is removed, but some of its components might be retained. Retained LVAD prosthetic material can lead to serious infection post heart transplant. We report 4 such cases. Our goal is to highlight the importance of complete prosthetic material removal at the time of cardiac transplant to prevent late-onset infection, especially in patients with preceding infection, but also in patients without evidence of LVAD infection prior to orthotopic heart transplantation.
