title: Regional Isolation Drives Bacterial Diversification within Cystic Fibrosis Lungs.
abstract: Bacterial lineages that chronically infect cystic fibrosis (CF) patients genetically diversify during infection. However, the mechanisms driving diversification are unknown. By dissecting ten CF lung pairs and studying ∼12,000 regional isolates, we were able to investigate whether clonally related Pseudomonas aeruginosa inhabiting different lung regions evolve independently and differ functionally. Phylogenetic analysis of genome sequences showed that regional isolation of P. aeruginosa drives divergent evolution. We investigated the consequences of regional evolution by studying isolates from mildly and severely diseased lung regions and found evolved differences in bacterial nutritional requirements, host defense and antibiotic resistance, and virulence due to hyperactivity of the type 3 secretion system. These findings suggest that bacterial intermixing is limited in CF lungs and that regional selective pressures may markedly differ. The findings also may explain how specialized bacterial variants arise during infection and raise the possibility that pathogen diversification occurs in other chronic infections characterized by spatially heterogeneous conditions.
authors: Department of Microbiology, University of Washington School of Medicine, Seattle, WA 98195, USA.
authors: Peter
authors: P
authors: Jorth
authors: Department of Medicine, University of Washington School of Medicine, Seattle, WA 98195, USA.
authors: Benjamin J
authors: BJ
authors: Staudinger
authors: Department of Genome Sciences, University of Washington School of Medicine, Seattle, WA 98195, USA.
authors: Xia
authors: X
authors: Wu
authors: Department of Medicine, University of Washington School of Medicine, Seattle, WA 98195, USA.
authors: Katherine B
authors: KB
authors: Hisert
authors: Department of Microbiology, University of Washington School of Medicine, Seattle, WA 98195, USA.
authors: Hillary
authors: H
authors: Hayden
authors: Department of Microbiology, University of Washington School of Medicine, Seattle, WA 98195, USA.
authors: Jayanthi
authors: J
authors: Garudathri
authors: Department of Microbiology, University of Washington School of Medicine, Seattle, WA 98195, USA.
authors: Christopher L
authors: CL
authors: Harding
authors: Department of Microbiology, University of Washington School of Medicine, Seattle, WA 98195, USA.
authors: Matthew C
authors: MC
authors: Radey
authors: Department of Microbiology, University of Washington School of Medicine, Seattle, WA 98195, USA.
authors: Amir
authors: A
authors: Rezayat
authors: Department of Microbiology, University of Washington School of Medicine, Seattle, WA 98195, USA.
authors: Gilbert
authors: G
authors: Bautista
authors: Department of Medicine, University of Washington School of Medicine, Seattle, WA 98195, USA.
authors: William R
authors: WR
authors: Berrington
authors: Department of Microbiology, University of Washington School of Medicine, Seattle, WA 98195, USA.
authors: Amanda F
authors: AF
authors: Goddard
authors: Department of Genome Sciences, University of Washington School of Medicine, Seattle, WA 98195, USA.
authors: Chunxiang
authors: C
authors: Zheng
authors: Department of Microbiology, University of Washington School of Medicine, Seattle, WA 98195, USA.
authors: Angus
authors: A
authors: Angermeyer
authors: Department of Microbiology, University of Washington School of Medicine, Seattle, WA 98195, USA.
authors: Mitchell J
authors: MJ
authors: Brittnacher
authors: Department of Genome Sciences, University of Washington School of Medicine, Seattle, WA 98195, USA.
authors: Jacob
authors: J
authors: Kitzman
authors: Department of Genome Sciences, University of Washington School of Medicine, Seattle, WA 98195, USA.
authors: Jay
authors: J
authors: Shendure
authors: Departments of Pathology and Laboratory Medicine, University of Washington School of Medicine, Seattle, WA 98195, USA.
authors: Corinne L
authors: CL
authors: Fligner
authors: Department of Microbiology, University of Washington School of Medicine, Seattle, WA 98195, USA.
authors: John
authors: J
authors: Mittler
authors: Department of Medicine, University of Washington School of Medicine, Seattle, WA 98195, USA.
authors: Moira L
authors: ML
authors: Aitken
authors: Department of Genome Sciences, University of Washington School of Medicine, Seattle, WA 98195, USA.
authors: Colin
authors: C
authors: Manoil
authors: Department of Genome Sciences, University of Washington School of Medicine, Seattle, WA 98195, USA.
authors: James E
authors: JE
authors: Bruce
authors: Department of Microbiology, University of Iowa School of Medicine, Iowa City, IA 52240, USA.
authors: Timothy L
authors: TL
authors: Yahr
authors: Department of Microbiology, University of Washington School of Medicine, Seattle, WA 98195, USA; Department of Medicine, University of Washington School of Medicine, Seattle, WA 98195, USA. Electronic address: singhpr@u.washington.edu.
authors: Pradeep K
authors: PK
authors: Singh
mesh_terms: D003550:Cystic Fibrosis / Q000150:complications*; D014644:Genetic Variation; D006801:Humans; D008168:Lung / Q000382:microbiology*; D008969:Molecular Sequence Data; D011552:Pseudomonas Infections / Q000382:microbiology*; D011550:Pseudomonas aeruginosa / Q000145:classification* / Q000235:genetics* / Q000302:isolation & purification; D017422:Sequence Analysis, DNA