Whole genome sequencing reveals the emergence of a Pseudomonas aeruginosa shared strain sub-lineage among patients treated within a single cystic fibrosis centre

- Whole genome sequencing reveals the emergence of a Pseudomonas aeruginosa shared strain sub-lineage among patients treated within a single cystic fibrosis centre.
- Background: Chronic lung infections caused by Pseudomonas aeruginosa are a significant cause of morbidity and mortality in people with cystic fibrosis (CF).
- The main aim of this study was to resolve the relationship of the emergent M3L7 sub-type within the AUST-02 group of strains using whole genome sequencing..
- Results: A whole genome core phylogeny of 63 isolates indicated that M3L7 is a monophyletic sub-lineage within the context of the broader AUST-02 group.
- Relatively short branch lengths connected all of the M3L7 isolates.
- A phylogeny based on nucleotide polymorphisms present across the genome showed that the chronological estimation of the most recent common ancestor was around 2001.
- SNP differences between sequential non-hypermutator M3L7 isolates collected 3 – 4 years apart from five patients suggested both continuous infection of the same strain and cross-infection of some M3L7 variants between patients.
- Full list of author information is available at the end of the article.
- 2018 Open Access This article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0.
- The majority of mortality and morbidity in people with CF is caused by chronic lung infection with Pseudomonas aeruginosa [1].
- lung transplantation, than other AUST-02 subtypes [16]..
- The aim of this study was to use WGS to reconstruct the population structure and resolve the relationship of the M3L7 sub-type within the AUST-02 group of strains..
- aeruginosa in Cystic Fibrosis (ACPinCF) study protocol [10].
- Of the 13 patients identified with M3L7 in six patients had no follow-up isolates available (five under- went lung transplantation and one moved interstate by 2011.
- Of the seven patients who had M3L7 infection in 2007–2008 and had samples collected in 2011, five remained infected with M3L7 in 2011 (Patients and 41), one (Patient 37) no longer had the M3L7 sub-type detected, while another (Patient 39) tested positive by the M3 allele-specific PCR, but the lasR sequence could not be determined because of suboptimal sequence quality (this isolate, AUS947, was subsequently confirmed as M3L7 by WGS in this study).
- An alignment of 30,811 core SNPs obtained from mapping against PAO1 was used to reconstruct the phylogeny of the 63 AUST-02 genome sequences.
- To determine the emergence of the M3L7 sub-type, Bayesian inference of the evolutionary rates was conducted using BEAST 1.8.2 [32].
- Among the different combinations of the molecular clock model (strict and constant relaxed lognor- mal), substitution model (HKY, GTR) and population size change (coalescent constant and exponential growth) models, the preferred combination of parameters selected based on stepping stone sampling was strict molecular clock, HKY substitution model with four discrete gamma- distributed rate categories, and exponential population size change.
- M3L7 is a distinct sub-lineage of the AUST-02 shared strain.
- On the basis of the whole-genome core phylogeny, the 63 AUST-02 isolates form two major discrete lineages (clades), M2 (n = 34) and M3 (n = 29), consistent with their possession of mexZ-2 (codon substitution, A38T) or mexZ-3 (codon substitution, T12N) alleles, respectively (Fig.
- 2007]) within the M3 clade form deep-branching relationships at the base of the lineage and do not harbour the lasR-7 allele (L7: 1 bp deletion, 438delG) that defines the M3L7 sub-type.
- Of the available AUST-02 sequences, isolate AUS970 [Patient 43.
- 2007], sequenced in this study, represented the AUST-02 genome that was most closely related to the M3L7 sub-lineage..
- M3L7 diverged recently from other AUST-02 shared strains.
- 1 Radial phylogeny of the AUST-02 genomes.
- The relationship of the M3L7 sub-lineage to other sequenced AUST-02 genomes from patients attending CF centres in Brisbane/Queensland (Red), Perth/Western Australia (Green) and Sydney/New South Wales (Blue: AUS853, AUS854) is shown.
- Taken together, these results support a single founder scenario in which a carrier of the M3L7 sub-type acted as a donor within a CF centre with subse- quent rapid dissemination in the resident CF population..
- Alternatively, dissemination of the M3L7 sub-type may have arisen through exposure to common environmental sources.
- aeruginosa infection of the CF airway [46, 47].
- 2 Time-calibrated phylogeny of the M3L7 sub-lineage.
- These findings highlight that short-term within-patient diversity of shared strains during chronic infection needs to be considered in light of the P.
- aeruginosa lung diversity of the local CF population as a whole..
- Clonal lineages are expected to accumulate mutations that enable adaptation of the bacterium to a specific environmental niche of a human host [8].
- A total of 44 shared SNPs and nine shared indels were acquired after divergence of the M3L7 sub-lineage from all other AUST-02 isolates of the M2 and M3 clades.
- resulting in a change of the amino acid sequence including two premature stop codons (Additional file 8: Table S4).
- Approxi- mately 50% of the non-synonymous mutations occurred in genes that encode proteins associated with virulence (e.g..
- 2007]) of the M2 clade.
- 2011]) and a previous study also observed the presence of the pro- phage in 9/11 M3L7 isolates collected in 2014 [17].
- There- fore, it is most likely that this prophage was present in the last common ancestor of the M3L7 sub-lineage and was vertically inherited.
- The prophage is inserted immediately adjacent to the mutS gene and a search of the putative prophage sequence using the PhaST webtool predicts a complete prophage that is only 9% identical to the P.
- The persistence of the AUST-02 shared strain in the CF population in Australia has led to the emergence of a monophyletic sub-lineage (M3L7) that is distinct from.
- The black squares indicate the PseudoCAP function of the gene.
- See Additional file 8: Table S4 for detailed information of the specific mutations.
- the M2 sub-lineage of AUST-02.
- Details of Pseudomonas aeruginosa isolates and genome assembly metrics used in this study.
- Geographic location of CF treatment centre where each isolate was obtained is shown on the right of the tree.
- Growth of the adult CF population at The Prince Charles Hospital between 2001 and 2015.
- CF: Cystic fibrosis.
- M3L1: Sub-lineage of the AUST-02 defined by mexZ (mexZ-3, M3) and lasR (lasR-1, L1) alleles.
- M3L7: Sub-lineage of the AUST-02 defined by mexZ (mexZ-3, M3) and lasR (lasR-7, L7) alleles.
- Cystic Fibrosis Group Scholarship.
- LJS is the recipient of The Shelley Shephard Memorial Scholarship.
- Funding bodies were not involved in the study design, analysis and interpretation of the results or in the writing of the manuscript..
- KRH, NLBZ, IL and SAB contributed to the interpretation of the bioinformatics analyses.
- 3 Adult Cystic Fibrosis Centre,.
- Cystic Fibrosis Trust.
- UK Cystic Fibrosis Registry 2014 Annual Report.
- Genetic adaptation by Pseudomonas aeruginosa to the airways of cystic fibrosis patients.
- Genomic variation among contemporary Pseudomonas aeruginosa isolates from chronically infected cystic fibrosis patients.
- Increased sputum amino acid concentrations and auxotrophy of Pseudomonas aeruginosa in severe cystic fibrosis lung disease.
- Pseudomonas aeruginosa population diversity and turnover in cystic fibrosis chronic infections.
- Convergent evolution and adaptation of Pseudomonas aeruginosa within patients with cystic fibrosis..
- Increased morbidity associated with chronic infection by an epidemic Pseudomonas aeruginosa strain in CF patients.
- Shared Pseudomonas aeruginosa genotypes are common in Australian cystic fibrosis centres.
- Increased treatment requirements of patients with cystic fibrosis who harbour a highly transmissible strain of Pseudomonas aeruginosa.
- Infection with transmissible strains of Pseudomonas aeruginosa and clinical outcomes in adults with cystic fibrosis.
- Pseudomonas aeruginosa in cystic fibrosis lung infections.
- The social network of cystic fibrosis Centre care and shared Pseudomonas aeruginosa strain infection: a cross-sectional analysis.
- Clonal strains of Pseudomonas aeruginosa in paediatric and adult cystic fibrosis units.
- Genotypic diversity within a single Pseudomonas aeruginosa strain commonly shared by Australian patients with cystic fibrosis.
- Within-host whole genome analysis of an antibiotic resistant Pseudomonas aeruginosa strain sub-type in cystic fibrosis.
- Evaluation of a new definition for chronic Pseudomonas aeruginosa infection in cystic fibrosis patients.
- Complete genome sequence of Pseudomonas aeruginosa PAO1, an opportunistic pathogen..
- Detection of a widespread clone of Pseudomonas aeruginosa in a pediatric cystic fibrosis clinic.
- Spread of a multiresistant strain of Pseudomonas aeruginosa in an adult cystic fibrosis clinic.
- Pseudomonas aeruginosa exhibits frequent recombination, but only a limited association between genotype and ecological setting.
- High frequency of hypermutable Pseudomonas aeruginosa in cystic fibrosis lung infection..
- Coexistence and within-host evolution of diversified lineages of hypermutable Pseudomonas aeruginosa in long-term cystic fibrosis infections.
- Divergent, coexisting Pseudomonas aeruginosa lineages in chronic cystic fibrosis lung infections.
- Viability of Pseudomonas aeruginosa in cough aerosols generated by persons with cystic fibrosis.
- Pseudomonas aeruginosa cross-infection among patients with cystic fibrosis during a winter camp.
- Selective sweeps and parallel Pathoadaptation drive Pseudomonas aeruginosa evolution in the cystic fibrosis lung.
- Pseudomonas aeruginosa evolutionary adaptation and diversification in cystic fibrosis chronic lung infections.
- PilS and PilR, a two- component transcriptional regulatory system controlling expression of type 4 fimbriae in Pseudomonas aeruginosa.
- Swarming of Pseudomonas aeruginosa is dependent on cell-to-cell signaling and requires flagella and pili.
- oligosaccharide of lipopolysaccharide affects flagella-mediated motility in Pseudomonas aeruginosa PAO1 via modulation of cell surface attachment..
- The capability of Pseudomonas aeruginosa to recruit zinc under conditions of limited metal availability is affected by inactivation of the ZnuABC transporter..
- Biosynthesis of pyochelin and dihydroaeruginoic acid requires the iron-regulated pchDCBA operon in Pseudomonas aeruginosa.
- Classification of OprD sequence and correlation with antimicrobial activity of carbapenem agents in Pseudomonas aeruginosa clinical isolates collected in Japan.
- Quantitative contributions of target alteration and decreased drug accumulation to Pseudomonas aeruginosa fluoroquinolone resistance.
- Identification of novel genes responsible for overexpression of ampC in Pseudomonas aeruginosa PAO1.
- Crystal structures of penicillin-binding protein 3 from Pseudomonas aeruginosa: comparison of native and antibiotic-bound forms.
- Polymyxin resistance of Pseudomonas aeruginosa phoQ mutants is dependent on additional two- component regulatory systems.
- PmrAB, a two-component regulatory system of Pseudomonas aeruginosa that modulates resistance to cationic antimicrobial peptides and addition of aminoarabinose to lipid a.
- Expression of the multidrug resistance operon mexA-mexB-oprM in Pseudomonas aeruginosa: mexR encodes a regulator of operon expression.
- Efflux unbalance in Pseudomonas aeruginosa isolates from cystic fibrosis patients.
- Mutations in PA2491 (mexS) promote MexT- dependent mexEF-oprN expression and multidrug resistance in a clinical strain of Pseudomonas aeruginosa.
- Characterization of MexT, the regulator of the MexE-MexF-OprN multidrug efflux system of Pseudomonas aeruginosa.
- Genome analysis of a transmissible lineage of Pseudomonas aeruginosa reveals pathoadaptive mutations and distinct evolutionary paths of hypermutators.
- Deletion and acquisition of genomic content during early stage adaptation of Pseudomonas aeruginosa to a human host environment

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