Objectives: Achromobacter spp. can cause chronic infections in the lungs of CF patients. One of the main mechanisms favouring the persistence of CF pathogens is hypermutation, in which defects in DNA repair processes promote an increased DNA mutation rate. In this study, longitudinal isolates were screened to verify the occurrence of hypermutators. Methods: 34 Achromobacter spp. clinical isolates were longitudinally collected over 3 years from 10 patients (CF Center of Verona, Italy) and underwent whole genome sequencing. Phylogenetic and variant analyses were performed. Presence of high impact mutations in mismatch repair (MMR) system genes, transition/transversion (ts/tv) ratio >3 and variant rate >3 were arbitrarily defined as criteria for hypermutation. Results: According to sequencing and phylogenetic analyses, 3 species of Achromobacter spp. were identified: A. xylosoxidans (25 isolates, 7 patients), A. rhulandii (4 isolates, 1 patient) and A. insuavis (5 isolates, 2 patients). MMR genes analysis showed that all A. rhulandii and A. insuavis genomes presented 2 copies of mutS gene while a single copy was detected in A. xylosoxidans genomes. Regardless of the species and number of mutS gene copies, 21 isolates (7 patients) overall were identified as hypermutators: they presented high impact mutations in either mutS, mutL, or mutT, high ts/tv ratio and increased mean yearly variant rate. Conclusions: Most of the enrolled patients (70%) with chronic infection presented hypermutators strains. Such a high prevalence confirms the occurrence and importance of hypermutation as an adaptive mechanism in Achromobacter spp. infection. Hypermutation could potentially influence the clinical outcomes and the efficacy of treatments, highlighting the need to clarify its impact in order to develop appropriate therapeutic regimens. Acknowledgments: This study was supported by the Italian CF Research Foundation (project FFC#18/2019).
P139 Hypermutation as an evolutionary mechanism for Achromobacter spp. in cystic fibrosis lung infection
Veschetti, L.;Sandri, A.;Passarelli Mantovani, R.;Melotti, P.;Malerba, G.;Lleo, M. M.
2020-01-01
Abstract
Objectives: Achromobacter spp. can cause chronic infections in the lungs of CF patients. One of the main mechanisms favouring the persistence of CF pathogens is hypermutation, in which defects in DNA repair processes promote an increased DNA mutation rate. In this study, longitudinal isolates were screened to verify the occurrence of hypermutators. Methods: 34 Achromobacter spp. clinical isolates were longitudinally collected over 3 years from 10 patients (CF Center of Verona, Italy) and underwent whole genome sequencing. Phylogenetic and variant analyses were performed. Presence of high impact mutations in mismatch repair (MMR) system genes, transition/transversion (ts/tv) ratio >3 and variant rate >3 were arbitrarily defined as criteria for hypermutation. Results: According to sequencing and phylogenetic analyses, 3 species of Achromobacter spp. were identified: A. xylosoxidans (25 isolates, 7 patients), A. rhulandii (4 isolates, 1 patient) and A. insuavis (5 isolates, 2 patients). MMR genes analysis showed that all A. rhulandii and A. insuavis genomes presented 2 copies of mutS gene while a single copy was detected in A. xylosoxidans genomes. Regardless of the species and number of mutS gene copies, 21 isolates (7 patients) overall were identified as hypermutators: they presented high impact mutations in either mutS, mutL, or mutT, high ts/tv ratio and increased mean yearly variant rate. Conclusions: Most of the enrolled patients (70%) with chronic infection presented hypermutators strains. Such a high prevalence confirms the occurrence and importance of hypermutation as an adaptive mechanism in Achromobacter spp. infection. Hypermutation could potentially influence the clinical outcomes and the efficacy of treatments, highlighting the need to clarify its impact in order to develop appropriate therapeutic regimens. Acknowledgments: This study was supported by the Italian CF Research Foundation (project FFC#18/2019).
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