A Naturally Occurring Rgg Variant in Serotype M3
            <i>Streptococcus pyogenes</i>
            Does Not Activate
            <i>speB</i>
            Expression Due to Altered Specificity of DNA Binding

Kappeler, Kyle V.; Anbalagan, Srivishnupriya; Дмитриев, А. В.; McDowell, Emily J.; Neely, Melody N.; Chaussee, Michael S.

doi:10.1128/iai.00373-09

Cited by 19 publications

(23 citation statements)

References 34 publications

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“…MGAS315 has a growth yield of approximately 1.0 absorbance unit at 600 nm (A 600 ) [35]. The mid-exponential phase was defined as a culture with an A 600 of approximately 0.5, which was attained by both the wild-type and the emm3 mutant strain after approximately 2.5 to 3.5 h of incubation.…”

Section: Methodsmentioning

confidence: 99%

Binding host proteins to the M protein contributes to the mortality associated with influenza–Streptococcus pyogenes superinfections

et al. 2017

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The mortality associated with influenza A virus (IAV) is often due to the development of secondary bacterial infections known as superinfections. The group A streptococcus (GAS) is a relatively uncommon cause of IAV superinfections, but the mortality of these infections is high. We used a murine model to determine whether the surface-localized GAS M protein contributes to the outcome of IAV-GAS superinfections. A comparison between wild-type GAS and an M protein mutant strain (emm3) showed that the M3 protein was essential to virulence. To determine whether the binding, or recruitment, of host proteins to the bacterial surface contributed to virulence, GAS was suspended with BALF collected from mice that had recovered from a sub-lethal infection with IAV. Following intranasal inoculation of naïve mice, the mortality associated with the wild-type strain, but not the emm3 mutant strain, was greater compared to mice inoculated with GAS suspended with either BALF from uninfected mice or PBS. Further analyses showed that both albumin and fibrinogen (Fg) were more abundant in the respiratory tract 8 days after IAV infection, that M3 bound both proteins to the bacterial surface, and that suspension of GAS with either protein increased GAS virulence in the absence of antecedent IAV infection. Overall, the results showed that M3 is essential to the virulence of GAS in an IAV superinfection and suggested that increased abundance of albumin and Fg in the respiratory tract following IAV infection enhanced host susceptibility to secondary GAS infection.

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Section: Methodsmentioning

confidence: 99%

Binding host proteins to the M protein contributes to the mortality associated with influenza–Streptococcus pyogenes superinfections

et al. 2017

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“…The SpeB AϪ phenotype has been shown to be a valid marker for CovRS mutations of invasive M1T1 GAS (12). However, mutations in ropB, the regulator of the speB gene, also can lead to the SpeB AϪ phenotype and commonly occur in clinical GAS isolates (35)(36)(37)(38). SpeB AϪ -causing mutations of CovRS, but not RopB, also enhance the expression of several virulence factors of M1T1 GAS, including the platelet-activating factor acetylhydrolase Sse (12)(13)(14)(15)(16)(17).…”

Section: Dnases Are Not Required For In Vivo Selection Of Spebmentioning

confidence: 99%

The Mga Regulon but Not Deoxyribonuclease Sda1 of Invasive M1T1 Group A Streptococcus Contributes to In Vivo Selection of CovRS Mutations and Resistance to Innate Immune Killing Mechanisms

Liu

Feng

et al. 2015

Infect Immun

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bInvasive M1T1 group A Streptococcus (GAS) can have a mutation in the regulatory system CovRS, and this mutation can render strains hypervirulent. Interestingly, via mechanisms that are not well understood, the host innate immune system's neutrophils select spontaneous M1T1 GAS CovRS hypervirulent mutants, thereby enhancing the pathogen's ability to evade immune killing. It has been reported that the DNase Sda1 is critical for the resistance of M1T1 strain 5448 to killing in human blood and provides pressure for in vivo selection of CovRS mutations. We reexamined the role of Sda1 in the selection of CovRS mutations and in GAS innate immune evasion. Deletion of sda1 or all DNase genes in M1T1 strain MGAS2221 did not alter emergence of CovRS mutants during murine infection. Deletion of sda1 in strain 5448 resulted in ⌬sda1 mutants with (5448 ⌬sda1 M؉ strain) and without (5448 ⌬sda1 M؊ strain) M protein production. The 5448 ⌬sda1 M؉ strain accumulated CovRS mutations in vivo and resisted killing in the bloodstream, whereas the 5448 ⌬sda1 M؊ strain lost in vivo selection of CovRS mutations and was sensitive to killing. The deletion of emm and a spontaneous Mga mutation in MGAS2221 reduced and prevented in vivo selection for CovRS mutants, respectively. Thus, in contrast to previous reports, Sda1 is not critical for in vivo selection of invasive M1T1 CovRS mutants and GAS resistance to innate immune killing mechanisms. In contrast, M protein and other Mga-regulated proteins contribute to the in vivo selection of M1T1 GAS CovRS mutants. These findings advance the understanding of the progression of invasive M1T1 GAS infections. The human pathogen group A Streptococcus (GAS) causes about 700 million cases of relatively mild, noninvasive pharyngitis and superficial skin infections annually. However, severe GAS infections, including severe invasive infections and acute rheumatic fever/rheumatic heart disease, can occur, causing approximately 517,000 deaths in the world each year (1). A globally disseminated M1T1 clone of serotype M1 GAS most frequently is associated with severe invasive infections in the United States (2-4). It is believed that the original M1T1 GAS clone evolved from the acquisitions of DNase Sda1-and superantigen SpeA-encoding prophages and an interserotype exchange of a 36-kb chromosomal region containing the toxin genes encoding NAD ϩ -glycohydrolase (NADase) and streptolysin O (SLO) with serotype M12 GAS (5-7). More recently, hypervirulent M1T1 GAS strains have been isolated, usually having mutations in the two-component regulatory system CovRS (also known as CsrRS) (8-12).CovRS is known to negatively regulate multiple virulence genes in GAS, including the capsule synthetase gene hasA, the interleukin-8 (IL-8)/CXC chemokine peptidase gene spyCEP, and the platelet-activating factor acetylhydrolase gene sse (13-18). Natural CovS mutations of invasive M1T1 isolates usually enhance the expression of these virulence genes and downregulate the production of the protease SpeB (SpeB AϪ , for the lack of the...

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“…A bioinformatic analysis of RopB-like proteins in various Gram-positive organisms identified 3 highly conserved amino acid residues in RopB, the substitution of any of which abolished group A streptococcal RopB function (30). Furthermore, a recent report demonstrated that an amino acid change in RopB (S103P) was found in a single group A streptococcal strain with decreased expression of speB (31). However, virulence studies performed to date involving RopB have used strains with insertional inactivation of ropB, and thus there is currently no information regarding the pathophysiologic consequences of naturally occurring single-amino-acid RopB variants (25,32).…”

Section: Introductionmentioning

confidence: 99%

Naturally occurring single amino acid replacements in a regulatory protein alter streptococcal gene expression and virulence in mice

Carroll¹,

Shelburne²,

Olsen³

et al. 2011

J. Clin. Invest.

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Infection with different strains of the same species of bacteria often results in vastly different clinical outcomes. Despite extensive investigation, the genetic basis of microbial strain-specific virulence remains poorly understood. Recent whole-genome sequencing has revealed that SNPs are the most prevalent form of genetic diversity among different strains of the same species of bacteria. For invasive serotype M3 group A streptococci (GAS) strains, the gene encoding regulator of proteinase B (RopB) has the highest frequency of SNPs. Here, we have determined that ropB polymorphisms alter RopB function and modulate GAS host-pathogen interactions. Sequencing of ropB in 171 invasive serotype M3 GAS strains identified 19 distinct ropB alleles. Inactivation of the ropB gene in strains producing distinct RopB variants had dramatically divergent effects on GAS global gene expression. Additionally, generation of isoallelic GAS strains differing only by a single amino acid in RopB confirmed that variant proteins affected transcript levels of the gene encoding streptococcal proteinase B, a major RopB-regulated virulence factor. Comparison of parental, RopB-inactivated, and RopB isoallelic strains in mouse infection models demonstrated that ropB polymorphisms influence GAS virulence and disease manifestations. These data detail a paradigm in which unbiased, whole-genome sequence analysis of populations of clinical bacterial isolates creates new avenues of productive investigation into the pathogenesis of common human infections.

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A Naturally Occurring Rgg Variant in Serotype M3 Streptococcus pyogenes Does Not Activate speB Expression Due to Altered Specificity of DNA Binding

Cited by 19 publications

References 34 publications

Binding host proteins to the M protein contributes to the mortality associated with influenza–Streptococcus pyogenes superinfections

Binding host proteins to the M protein contributes to the mortality associated with influenza–Streptococcus pyogenes superinfections

The Mga Regulon but Not Deoxyribonuclease Sda1 of Invasive M1T1 Group A Streptococcus Contributes to In Vivo Selection of CovRS Mutations and Resistance to Innate Immune Killing Mechanisms

Naturally occurring single amino acid replacements in a regulatory protein alter streptococcal gene expression and virulence in mice

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