Genome-wide molecular dissection of serotype M3 group A Streptococcus strains causing two epidemics of invasive infections

Abstract

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.population genetics ͉ evolution ͉ phage ͉ subclone

No increased risk of valvular heart disease in adult poststreptococcal reactive arthritis

“…Traditionally this "rheumatogenecity" has been considered to be a feature of strains belonging to certain M serotypes (the serotypes M3 and M18 have been related to ARF). Recent genome-wide analyses of group A streptococci have demonstrated that the heterogeneity in disease severity caused by group A streptococci is mediated by genetic variation in a signal transduction system that affects the expression of virulence factors (36,37). The combination of a susceptible host and a virulent group A Streptococcus may induce an exaggerated immune response, leading to valvular heart disease.…”

Group A Streptococcus Activates Type I Interferon Production and MyD88-dependent Signaling without Involvement of TLR2, TLR4, and TLR9

“…The heterogeneity of GAS diseases arises in part from the high diversity of GAS-mediated host-pathogen interactions in which virulence factors, GAS genome composition, prophage DNA, and plasticity of the GAS transcriptome play key roles (2,(61)(62)(63)(64). A major factor influencing the severity of GAS infections is also the genetic inventory of the host.…”

Toward a Genome-Wide Systems Biology Analysis of Host-Pathogen Interactions in Group A Streptococcus

“…Collectively, acquisition or loss of prophages, allelic variation in chromosomal genes, expansion of subclone populations, and introduction of new subclone variants were shown to contribute to peaks of infection and different infection types. 49 One finding from this study was particularly noteworthy and provided key insight into a potential mechanism accounting for clone emergence. Molecular genetic analysis, combined with immunological studies, implicated a 4-amino acid duplication in the extreme N-terminus of M protein as a factor contributing to rapid clone emergence.…”

“…To test the hypothesis, 255 contemporary M3 strains obtained from an 11-year population-based surveillance study of invasive disease in Ontario, Canada, were analyzed. 49 Genetic diversity in these strains was investigated by several state-of-the-art methods, including DNA-DNA microarray and whole-genome PCR tiling. The core genome of all strains was identical in gene content.…”

“…35 We conducted a molecular genetic dissection of two epidemic waves by using multipronged approach that involved sequencing the genome of a relevant strain, performing functional analysis of novel extracellular proteins encoded by the genome, and then using comparative genomic analysis of the strains. 49 To initiate this line of investigation, the genome of a strain isolated from a patient with invasive disease was sequenced. 23 As found for other GAS strains, prophagelike elements accounted for the great majority of variation in gene content relative to other GAS genomes.…”