Genome sequence and comparative microarray analysis of serotype M18 group A Streptococcus strains associated with acute rheumatic fever outbreaks

Abstract

Acute rheumatic fever (ARF), a sequelae of group A Streptococcus (GAS) infection, is the most common cause of preventable childhood heart disease worldwide. The molecular basis of ARF and the subsequent rheumatic heart disease are poorly understood. Serotype M18 GAS strains have been associated for decades with ARF outbreaks in the U.S. As a first step toward gaining new insight into ARF pathogenesis, we sequenced the genome of strain MGAS8232, a serotype M18 organism isolated from a patient with ARF. The genome is a circular chromosome of 1,895,017 bp, and it shares 1.7 Mb of closely related genetic material with strain SF370 (a sequenced serotype M1 strain). Strain MGAS8232 has 178 ORFs absent in SF370. Phages, phage-like elements, and insertion sequences are the major sources of variation between the genomes. The genomes of strain MGAS8232 and SF370 encode many of the same proven or putative virulence factors. Importantly, strain MGAS8232 has genes encoding many additional secreted proteins involved in human-GAS interactions, including streptococcal pyrogenic exotoxin A (scarlet fever toxin) and two uncharacterized pyrogenic exotoxin homologues, all phage-associated. DNA microarray analysis of 36 serotype M18 strains from diverse localities showed that most regions of variation were phages or phage-like elements. Two epidemics of ARF occurring 12 years apart in Salt Lake City, UT, were caused by serotype M18 strains that were genetically identical, or nearly so. Our analysis provides a critical foundation for accelerated research into ARF pathogenesis and a molecular framework to study the plasticity of GAS genomes.Streptococcus pyogenes ͉ GAS ͉ complete genome sequence ͉ DNA microarray ͉ genomic diversity

Evolutionary pathway to increased virulence and epidemic group A Streptococcus disease derived from 3,615 genome sequences

“…ICEs (25). Common GAS prophage-encoded virulence factors include pyrogenic toxin superantigens, extracellular DNases, and a secreted phospholipase A2 (22)(23)(24)(25)(26)(27)(28)(29)(30)(31)(32)(33). GAS ICE-encoded antimicrobial agents typically include those mediating resistance to tetracycline or macrolides (34).…”

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

“…Virtually all GAS prophages encode one or two proven or putative extracellular virulence factors such as pyrogenic toxin superantigens (PTSAgs), DNAses, novel phospholipase A 2 (SlaA), efflux pump responsible for resistance to macrolide antibiotics, and a novel cell wall-anchored protein hypothesized to be an adhesin. [23][24][25][26][27][28][29] Many of these prophage-associated virulence factor genes were unknown before their discovery by GAS genome sequencing projects. Additional specific discoveries revealed by the genome sequencing projects are described below.…”

“…As a first step toward gaining new insight into ARF pathogenesis, we sequenced the genome of a M18 strain cultured from a patient with ARF. 24 In addition, we used DNA microarray analysis to compare the genomes of 36 M18 strains, including organisms cultured from patients with ARF and pharyngitis during two epidemics of ARF in Salt Lake City, UT. 24,31 Many genes are unique to serotype M18 strains.…”

“…24 In addition, we used DNA microarray analysis to compare the genomes of 36 M18 strains, including organisms cultured from patients with ARF and pharyngitis during two epidemics of ARF in Salt Lake City, UT. 24,31 Many genes are unique to serotype M18 strains. Importantly, this serotype has genes encoding unique secreted proteins involved in human-GAS interactions, including two previously uncharacterized novel PTSAgs that are encoded by a prophage.…”

“…[22][23][24][25][26][27][28] The availability of genome sequences of M protein serotypes causing distinct diseases has yielded a tremendous amount of new information important for a systems biology approach to pathogenesis research.…”