Contemporary Pharyngeal and Invasive emm1 and Invasive emm12 Group A Streptococcus Isolates Exhibit Similar In Vivo Selection for CovRS Mutants in Mice.

Wenchao Feng,Benfang Lei,Mengyao Liu,Ferric C Fang,Rossana Yiu,Daniel G Chen,Michael S Chaussee

doi:10.1371/journal.pone.0162742

Abstract

Group A Streptococcus (GAS) causes diverse infections ranging from common pharyngitis to rare severe invasive infections. Invasive GAS isolates can have natural mutations in the virulence regulator CovRS, which result in enhanced expression of multiple virulence genes, suppressed the expression of the protease SpeB, and increased virulence. It is believed that CovRS mutations arise during human infections with GAS carrying wild-type CovRS and are not transmissible. CovRS mutants of invasive GAS of the emm1 genotype arise readily during experimental infection in mice. It is possible that invasive GAS arises from pharyngeal GAS through rare genetic mutations that confer the capacity of mutated GAS to acquire covRS mutations during infection. The objective of this study was to determine whether contemporary pharyngeal emm1 GAS isolates have a reduced propensity to acquire CovRS mutations in vivo compared with invasive emm1 GAS and whether emm3, emm12, and emm28 GAS acquire CovRS mutants in mouse infection. The propensity of invasive and pharyngeal emm1 and invasive emm3, emm12, and emm28 SpeBA+ isolates to acquire variants with the SpeBA- phenotype was determined during subcutaneous infection of mice. The majority of both invasive and pharyngeal emm1 SpeBA+ isolates and two of three emm12 isolates, but not emm3 and emm28 isolates, were found to acquire SpeBA- variants during skin infection in mice. All analyzed SpeBA- variants of emm1 and emm12 GAS from the mouse infection acquired covRS mutations and produced more platelet-activating factor acetylhydrolase SsE. Thus, contemporary invasive and pharyngeal emm1 GAS isolates and emm12 GAS have a similar capacity to acquire covRS mutations in vivo. The rarity of severe invasive infections caused by GAS does not appear to be attributable to a reduced ability of pharyngeal isolates to acquire CovRS mutations.

Highlights

Group A Streptococcus (GAS) is a major human pathogen that causes both relatively mild pharyngitis and superficial skin infections and potentially lethal, severe invasive infections [1]
The objective of this study was to determine whether pharyngeal emm1 GAS isolates are able to acquire CovRS mutations as readily as invasive M1 isolates in vivo and whether emm3, emm12, and emm28 GAS can acquire CovRS mutants in mouse infection
We have reported that the SpeBA- phenotype is a reliable indicator for CovRS mutations of MGAS2221 in subcutaneous infection of mice [17], CovRS mutations may not be the only cause of the SpeBA- phenotype

Summary

Introduction

Group A Streptococcus (GAS) is a major human pathogen that causes both relatively mild pharyngitis and superficial skin infections and potentially lethal, severe invasive infections [1]. The reemergence of severe invasive GAS infections in the 1980s is associated with the emergence of a virulent M1T1 clone of emm GAS [3,4,5] and virulent emm GAS [6]. The M1T1 clone of emm GAS is evolved by the acquisition of DNase Sda1- and superantigen SpeA-encoding prophages and the replacement of a 36-kb chromosomal region of pre-1980 M1 GAS with that of emm GAS that contains the NADase and streptolysin O genes [7,8,9]. Since 2000, M89 GAS without the genes for synthesis of the hyaluronic acid capsule has emerged to cause severe invasive infections in the United Kingdom, as well as the United States, Finland, Iceland, and Portugal [10,11,12]

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