Genome-wide molecular dissection of serotype M3 group A Streptococcus strains causing two epidemics of invasive infections.
Molecular factors that contribute to the emergence of new virulent bacterial subclones and epidemics are poorly understood. We hypothesized that analysis of a population-based strain sample of serotype M3 group A Streptococcus (GAS) recovered from patients with invasive infection by using genome-wide investigative methods would provide new insight into this fundamental infectious disease problem. Serotype M3 GAS strains (n = 255) cultured from patients in Ontario, Canada, over 11 years and representing two distinct infection peaks were studied. Genetic diversity was indexed by pulsed-field gel electrophoresis, DNA-DNA microarray, whole-genome PCR scanning, prophage genotyping, targeted gene sequencing, and single-nucleotide polymorphism genotyping. All variation in gene content was attributable to acquisition or loss of prophages, a molecular process that generated unique combinations of proven or putative virulence genes. Distinct serotype M3 genotypes experienced rapid population expansion and caused infections that differed significantly in character and severity. Molecular genetic analysis, combined with immunologic studies, implicated a 4-aa duplication in the extreme N terminus of M protein as a factor contributing to an epidemic wave of serotype M3 invasive infections. This finding has implications for GAS vaccine research. Genome-wide analysis of population-based strain samples cultured from clinically well defined patients is crucial for understanding the molecular events underlying bacterial epidemics.
Beres
Stephen B
SB
Laboratory of Human Bacterial Pathogenesis, Rocky Mountain Laboratories, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Hamilton, MT 59840, USA.
Sylva
Gail L
GL
Sturdevant
Daniel E
DE
Granville
Chanel N
CN
Liu
Mengyao
M
Ricklefs
Stacy M
SM
Whitney
Adeline R
AR
Parkins
Larye D
LD
Hoe
Nancy P
NP
Adams
Gerald J
GJ
Low
Donald E
DE
DeLeo
Frank R
FR
McGeer
Allison
A
Musser
James M
JM
D000942:Antigens, Bacterial / Q000235:genetics / Q000502:physiology; D001425:Bacterial Outer Membrane Proteins / Q000235:genetics / Q000502:physiology; D001426:Bacterial Proteins / Q000235:genetics; D002170:Canada / Q000453:epidemiology; D002352:Carrier Proteins / Q000235:genetics / Q000502:physiology; D002869:Chromosome Aberrations; D004196:Disease Outbreaks; D014644:Genetic Variation; D016680:Genome, Bacterial; D023281:Genomics / Q000379:methods; D005838:Genotype; D006801:Humans; D020641:Polymorphism, Single Nucleotide; D011159:Population Surveillance; D017421:Sequence Analysis; D013290:Streptococcal Infections / Q000453:epidemiology* / Q000821:virology; D013297:Streptococcus pyogenes / Q000235:genetics* / Q000276:immunology / Q000472:pathogenicity; D014774:Virulence / Q000235:genetics; D037521:Virulence Factors / Q000235:genetics
D000942:Antigens, Bacterial; D001425:Bacterial Outer Membrane Proteins; D001426:Bacterial Proteins; D002352:Carrier Proteins; D037521:Virulence Factors; C014689:streptococcal M protein