Full-Genome Dissection of an Epidemic of Severe Invasive Disease Caused by a Hypervirulent, Recently Emerged Clone of Group A Streptococcus

Fittipaldi, Nahuel; Beres, Stephen B.; Olsen, Randall J.; Kapur, Vivek; Shea, Patrick R.; Watkins, M. Ebru; Cantu, Concepcion; Laucirica, Daniel R.; Jenkins, Leslie; Flores, Anthony R.; Lovgren, Marguerite; Ardanuy, Carmen; Liñares, Josefina; Low, Donald E.; Tyrrell, Gregory J.; Musser, James M.

doi:10.1016/j.ajpath.2011.12.037

Cited by 72 publications

(129 citation statements)

References 50 publications

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“…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).…”

Section: Resultsmentioning

confidence: 99%

“…DNA extracted from each of the 3,615 strains was prepared for multiplexed sequencing, using Illumina Nextera XT kits (27). Genome sequence data were obtained predominantly with an Illumina HiSeq2000 instrument according to the manufacturer's instructions.…”

Section: Methodsmentioning

confidence: 99%

“…We next tested the hypothesis that strain MGAS2221 was significantly more virulent during invasive infection, as assessed using a well-described nonhuman primate model of necrotizing fasciitis (27,44,45). Significantly more bacteria were recovered from animals infected with MGAS2221 compared with those infected with strain SF370 (Fig.…”

Section: Molecular Evolutionary Genetics Of Contemporary M1 Clone Emementioning

confidence: 99%

“…To directly test this hypothesis, we used two nonhuman primate models of infection to compare the virulence of preresurgence reference strain SF370 with postresurgence strain MGAS2221. The cynomolgus macaque has been used extensively for experimental studies because it closely approximates human-GAS molecular interactions (27,(44)(45)(46). Two groups of monkeys were infected in the upper respiratory tract with either strain SF370 or strain MGAS2221 and monitored for 21 d. Strain SF370 was used because it was the first GAS genome to be sequenced, has been used extensively in studies over the last 13 y, and contains the old variant of the 36-kb region of recombination.…”

Section: Molecular Evolutionary Genetics Of Contemporary M1 Clone Emementioning

confidence: 99%

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

Nasser

Beres

Olsen

et al. 2014

Proc. Natl. Acad. Sci. U.S.A.

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236

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We sequenced the genomes of 3,615 strains of serotype Emm protein 1 (M1) group A Streptococcus to unravel the nature and timing of molecular events contributing to the emergence, dissemination, and genetic diversification of an unusually virulent clone that now causes epidemic human infections worldwide. We discovered that the contemporary epidemic clone emerged in stepwise fashion from a precursor cell that first contained the phage encoding an extracellular DNase virulence factor (streptococcal DNase D2, SdaD2) and subsequently acquired the phage encoding the SpeA1 variant of the streptococcal pyrogenic exotoxin A superantigen. The SpeA2 toxin variant evolved from SpeA1 by a single-nucleotide change in the M1 progenitor strain before acquisition by horizontal gene transfer of a large chromosomal region encoding secreted toxins NAD + -glycohydrolase and streptolysin O. Acquisition of this 36-kb region in the early 1980s into just one cell containing the phage-encoded sdaD2 and speA2 genes was the final major molecular event preceding the emergence and rapid intercontinental spread of the contemporary epidemic clone. Thus, we resolve a decades-old controversy about the type and sequence of genomic alterations that produced this explosive epidemic. Analysis of comprehensive, population-based contemporary invasive strains from seven countries identified strong patterns of temporal population structure. Compared with a preepidemic reference strain, the contemporary clone is significantly more virulent in nonhuman primate models of pharyngitis and necrotizing fasciitis. A key finding is that the molecular evolutionary events transpiring in just one bacterial cell ultimately have produced millions of human infections worldwide.pathogenesis | phylogeography | mobile genetic element | flesh-eating disease | molecular clock

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Section: Resultsmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

Section: Molecular Evolutionary Genetics Of Contemporary M1 Clone Emementioning

confidence: 99%

Section: Molecular Evolutionary Genetics Of Contemporary M1 Clone Emementioning

confidence: 99%

See 2 more Smart Citations

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

Nasser

Beres

Olsen

et al. 2014

Proc. Natl. Acad. Sci. U.S.A.

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236

343

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show abstract

“…Thus, it was a best-case scenario. Serotype emm59 GAS organisms are typically an uncommon cause of human disease (7)(8)(9); however, a hypervirulent clone recently arose, and its progeny spread rapidly throughout Canada, causing many hundreds of severe invasive infections (10)(11)(12). The surveillance data from the Centers for Disease Control and Prevention now indicate that the frequency of emm59 GAS infections is increasing in some areas of the United States, particularly Minnesota (13).…”

mentioning

confidence: 99%

Clinical Laboratory Response to a Mock Outbreak of Invasive Bacterial Infections: a Preparedness Study

et al. 2014

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Large hospital-based clinical laboratories must be prepared to rapidly investigate potential infectious disease outbreaks. To challenge the ability of our molecular diagnostics laboratory to use whole-genome sequencing in a potential outbreak scenario and identify impediments to these efforts, we studied 84 invasive serotype emm59 group A streptococcus (GAS) strains collected in the United States. We performed a rapid-response exercise to the mock outbreak scenario using whole-genome sequencing, genome-wide transcript analysis, and mouse virulence studies. The protocol changes installed in response to the lessons learned were tested in a second iteration. The initial investigation was completed in 9 days. Whole-genome sequencing showed that the invasive infections were caused by multiple subclones of epidemic emm59 GAS strains likely spread to the United States from Canada. The phylogenetic tree showed a strong temporal-spatial structure with diversity in mobile genetic element content, features that are useful for identifying closely related strains and possible transmission events. The genome data informed the epidemiology, identifying multiple patients who likely acquired the organisms through direct person-to-person transmission. Transcriptome analysis unexpectedly revealed significantly altered expression of genes encoding a two-component regulator and the hyaluronic acid capsule virulence factor. Mouse infection studies confirmed a high-virulence capacity of these emm59 organisms. Whole-genome sequencing, coupled with transcriptome analysis and animal virulence studies, can be rapidly performed in a clinical environment to effectively contribute to patient care decisions and public health maneuvers.

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Pathogenesis of Streptococcus in Humans

Creti

Gherardi

Berardi³

et al. 2015

Human Emerging and Re‐emerging Infections

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Full-Genome Dissection of an Epidemic of Severe Invasive Disease Caused by a Hypervirulent, Recently Emerged Clone of Group A Streptococcus

Cited by 72 publications

References 50 publications

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

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

Clinical Laboratory Response to a Mock Outbreak of Invasive Bacterial Infections: a Preparedness Study

Pathogenesis of Streptococcus in Humans

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