Small mutations in Bordetella pertussis are associated with selective sweeps

PLoS One. 2012;7(9):e46407. doi: 10.1371/journal.pone.0046407. Epub 2012 Sep 28.

Abstract

Bordetella pertussis is the causative agent of pertussis, a highly contagious disease of the human respiratory tract. Despite high vaccination coverage, pertussis has resurged and has become one of the most prevalent vaccine-preventable diseases in developed countries. We have proposed that both waning immunity and pathogen adaptation have contributed to the persistence and resurgence of pertussis. Allelic variation has been found in virulence-associated genes coding for the pertussis toxin A subunit (ptxA), pertactin (prn), serotype 2 fimbriae (fim2), serotype 3 fimbriae (fim3) and the promoter for pertussis toxin (ptxP). In this study, we investigated how more than 60 years of vaccination has affected the Dutch B. pertussis population by combining data from phylogeny, genomics and temporal trends in strain frequencies. Our main focus was on the ptxA, prn, fim3 and ptxP genes. However, we also compared the genomes of 11 Dutch strains belonging to successful lineages. Our results showed that, between 1949 and 2010, the Dutch B. pertussis population has undergone as least four selective sweeps that were associated with small mutations in ptxA, prn, fim3 and ptxP. Phylogenetic analysis revealed a stepwise adaptation in which mutations accumulated clonally. Genomic analysis revealed a number of additional mutations which may have a contributed to the selective sweeps. Five large deletions were identified which were fixed in the pathogen population. However, only one was linked to a selective sweep. No evidence was found for a role of gene acquisition in pathogen adaptation. Our results suggest that the B. pertussis gene repertoire is already well adapted to its current niche and required only fine tuning to persist in the face of vaccination. Further, this work shows that small mutations, even single SNPs, can drive large changes in the populations of bacterial pathogens within a time span of six to 19 years.

MeSH terms

  • Adaptation, Biological / genetics*
  • Alleles
  • Antigens, Bacterial / genetics
  • Antigens, Bacterial / immunology
  • Bacterial Outer Membrane Proteins / genetics
  • Bacterial Outer Membrane Proteins / immunology
  • Base Sequence
  • Bordetella pertussis / classification
  • Bordetella pertussis / genetics*
  • Bordetella pertussis / pathogenicity*
  • Fimbriae Proteins / genetics
  • Fimbriae Proteins / immunology
  • Gene Frequency
  • Genetic Variation
  • Humans
  • Molecular Sequence Data
  • Mutation*
  • Netherlands / epidemiology
  • Pertussis Toxin / genetics
  • Pertussis Toxin / immunology
  • Pertussis Vaccine / administration & dosage
  • Pertussis Vaccine / immunology
  • Phylogeny
  • Polymorphism, Single Nucleotide
  • Promoter Regions, Genetic
  • Serotyping
  • Vaccination*
  • Virulence
  • Virulence Factors, Bordetella / genetics
  • Virulence Factors, Bordetella / immunology
  • Whooping Cough / epidemiology
  • Whooping Cough / immunology
  • Whooping Cough / microbiology
  • Whooping Cough / prevention & control*

Substances

  • Antigens, Bacterial
  • Bacterial Outer Membrane Proteins
  • Pertussis Vaccine
  • Virulence Factors, Bordetella
  • fim2 protein, Bordetella
  • fim3 protein, Bordetella
  • Fimbriae Proteins
  • pertactin
  • Pertussis Toxin

Associated data

  • GENBANK/CAA52217

Grants and funding

The authors have no support or funding to report.