Population and Whole Genome Sequence Based Characterization of Invasive Group A Streptococci Recovered in the United States during 2015
Authors: Chochua Sopio , Metcalf Ben J. , Li Zhongya , Rivers Joy , Mathis Saundra , Jackson Delois , Gertz Robert E. , Srinivasan Velusamy , Lynfield Ruth , Van Beneden Chris , McGee Lesley , Beall Bernard 
Published: September 2017

Group A streptococci (GAS) are genetically diverse. Determination of strain features can reveal associations with disease and resistance and assist in vaccine formulation. We employed whole-genome sequence (WGS)-based characterization of 1,454 invasive GAS isolates recovered in 2015 by Active Bacterial Core Surveillance and performed conventional antimicrobial susceptibility testing. Predictions were made for genotype, GAS carbohydrate, antimicrobial resistance, surface proteins (M family, fibronectin binding, T, R28), secreted virulence proteins (Sda1, Sic, exotoxins), hyaluronate capsule, and an upregulated
nga
operon (encodes NADase and streptolysin O) promoter (Pnga3). Sixty-four M protein gene (
emm
) types were identified among 69 clonal complexes (CCs), including one CC of
Streptococcus dysgalactiae
subsp.
equisimilis
.
emm
types predicted the presence or absence of active
sof
determinants and were segregated into
sof-
positive or
sof-
negative genetic complexes. Only one “
emm
type switch” between strains was apparent.
sof
-negative strains showed a propensity to cause infections in the first quarter of the year, while
sof

+

strain infections were more likely in summer. Of 1,454 isolates, 808 (55.6%) were Pnga3 positive and 637 (78.9%) were accounted for by types
emm1
,
emm89
, and
emm12
. Theoretical coverage of a 30-valent M vaccine combined with an M-related protein (Mrp) vaccine encompassed 98% of the isolates. WGS data predicted that 15.3, 13.8, 12.7, and 0.6% of the isolates were nonsusceptible to tetracycline, erythromycin plus clindamycin, erythromycin, and fluoroquinolones, respectively, with only 19 discordant phenotypic results. Close phylogenetic clustering of
emm59
isolates was consistent with recent regional emergence. This study revealed strain traits informative for GAS disease incidence tracking, outbreak detection, vaccine strategy, and antimicrobial therapy.

IMPORTANCE
The current population-based WGS data from GAS strains causing invasive disease in the United States provide insights important for prevention and control strategies. Strain distribution data support recently proposed multivalent M type-specific and conserved M-like protein vaccine formulations that could potentially protect against nearly all invasive U.S. strains. The three most prevalent clonal complexes share key polymorphisms in the
nga
operon encoding two secreted virulence factors (NADase and streptolysin O) that have been previously associated with high strain virulence and transmissibility. We find that
Streptococcus pyogenes
is phylogenetically subdivided into loosely defined multilocus sequence type-based clusters consisting of solely
sof-
negative or
sof-
positive strains; with
sof-
negative strains demonstrating differential seasonal preference for infection, consistent with the recently demonstrated differential seasonal preference based on phylogenetic clustering of full-length M proteins. This might relate to the differences in GAS strain compositions found in different geographic settings and could further inform prevention strategies.