CF metagenomics literature review

Folkesson et al, doi:10.1038/nrmicro2907

• 1500 possible mutations in CFTR
• In 1974, median age of death was 8 years. Now 40 years.
• Microbial communities: studies focus on P. auruginosa, S. aureus, H. influenzae, B. cepacia complex
  • PA infections persist and become chronic in patients with CF
  • Genetic studies have shown most of the initial colonizing strains are unique, originate from unidentified environmental reservoirs
  • 60-70% patients with CF are infected by PA by age of 20
  • Mode of acquisition unknown
  • Chronic airway infection usually preceded by period of recurrent, intermittent colonization of the airway
  • Aggressive antibiotic therapy delays chronic infection
  • Re-infection can be with other genotype, but 25% same genotype
  • Reservoir: paranasal sinuses?
  • For unknown reasons, colonisation transitions into a chronic infection
  • Chronic infection
    • Continuous growth of PA
    • Development of PA specific antibodies - higher degree of inflammation
    • Changes in gene expression: algTU regulon
    • Antibiotic resistance
    • Production of reactive oxygen species and reactive nitrogen intermediates by the host > stress on bacteria > inflammation
  • PA in chronic infection
    • Colony morphotype variants
    • Hypermutability
    • Range of antibiotic resistance phenotypes
    • Generalising conclusions concerning the population structure of PA in the CF airway should be considered with caution, as they are often based on investigations of single bacterial isolates from samples taken at different time-points.
    • Cramer, et al. PA14 clonal complex: only 15 SNPs accumulated over a period of 15 years.
    • Hypermutators seen
  • Copenhagen study
    • SNPs accumulating linearly, 7.2x10^-11 SNPs per bp per generation) - 180SNPs from isolates in 1973 to patient sampled 35 years later.
    • Rapid adaptation at start of infection, then phenotypic stability and signal of negative selection
  • Five hypotheses for future investigations
    • Sinuses of patients with CF might act as protected reservoirs for the adaptation of PA to the lung
    • Limitedn umber of mutations may be necessary to transform opportunistic pathogen to persistent pathogen
    • Adaptive changes in bacterial population might occur long before clinical criteria of chronic infection are met
    • Evoutionary dynanmics of PA

Ideas

• Metagenomics approach for understanding PA population in the lung
• Use long range insert libraries for better haplotype construction
• Multiple sample preps for differnet coverage profiles
• Different insert sizes

Burns JL, et al. J Infect Dis 184 444-452