SpxA1 and SpxA2 Act Coordinately To Fine-Tune Stress Responses and Virulence in <italic toggle="yes">Streptococcus pyogenes</italic>

ABSTRACT SpxA is a unique transcriptional regulator highly conserved among members of the phylum Firmicutes that binds RNA polymerase and can act as an antiactivator. Why some Firmicutes members have two highly similar SpxA paralogs is not understood. Here, we show that the SpxA paralogs of the path...

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Autores principales:	Gary C. Port, Zachary T. Cusumano, Paul R. Tumminello, Michael G. Caparon
Formato:	article
Lenguaje:	EN
Publicado:	American Society for Microbiology 2017
Materias:	Microbiology QR1-502
Acceso en línea:	https://doaj.org/article/7d9324830c88471984a4b367b730af2a
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spelling	oai:doaj.org-article:7d9324830c88471984a4b367b730af2a2021-11-15T15:50:59ZSpxA1 and SpxA2 Act Coordinately To Fine-Tune Stress Responses and Virulence in <italic toggle="yes">Streptococcus pyogenes</italic>10.1128/mBio.00288-172150-7511https://doaj.org/article/7d9324830c88471984a4b367b730af2a2017-05-01T00:00:00Zhttps://journals.asm.org/doi/10.1128/mBio.00288-17https://doaj.org/toc/2150-7511ABSTRACT SpxA is a unique transcriptional regulator highly conserved among members of the phylum Firmicutes that binds RNA polymerase and can act as an antiactivator. Why some Firmicutes members have two highly similar SpxA paralogs is not understood. Here, we show that the SpxA paralogs of the pathogen Streptococcus pyogenes, SpxA1 and SpxA2, act coordinately to regulate virulence by fine-tuning toxin expression and stress resistance. Construction and analysis of mutants revealed that SpxA1− mutants were defective for growth under aerobic conditions, while SpxA2− mutants had severely attenuated responses to multiple stresses, including thermal and oxidative stresses. SpxA1− mutants had enhanced resistance to the cationic antimicrobial molecule polymyxin B, while SpxA2− mutants were more sensitive. In a murine model of soft tissue infection, a SpxA1− mutant was highly attenuated. In contrast, the highly stress-sensitive SpxA2− mutant was hypervirulent, exhibiting more extensive tissue damage and a greater bacterial burden than the wild-type strain. SpxA1− attenuation was associated with reduced expression of several toxins, including the SpeB cysteine protease. In contrast, SpxA2− hypervirulence correlated with toxin overexpression and could be suppressed to wild-type levels by deletion of speB. These data show that SpxA1 and SpxA2 have opposing roles in virulence and stress resistance, suggesting that they act coordinately to fine-tune toxin expression in response to stress. SpxA2− hypervirulence also shows that stress resistance is not always essential for S. pyogenes pathogenesis in soft tissue. IMPORTANCE For many pathogens, it is generally assumed that stress resistance is essential for pathogenesis. For Streptococcus pyogenes, environmental stress is also used as a signal to alter toxin expression. The amount of stress likely informs the bacterium of the strength of the host’s defense response, allowing it to adjust its toxin expression to produce the ideal amount of tissue damage, balancing between too little damage, which will result in its elimination, and too much damage, which will debilitate the host. Here we identify components of a genetic circuit involved in stress resistance and toxin expression that has a fine-tuning function in tissue damage. The circuit consists of two versions of the protein SpxA that regulate transcription and are highly similar but have opposing effects on the severity of soft tissue damage. These results will help us understand how virulence is fine-tuned in other pathogens that have two SpxA proteins.Gary C. PortZachary T. CusumanoPaul R. TumminelloMichael G. CaparonAmerican Society for MicrobiologyarticleMicrobiologyQR1-502ENmBio, Vol 8, Iss 2 (2017)
institution	DOAJ
collection	DOAJ
language	EN
topic	Microbiology QR1-502
spellingShingle	Microbiology QR1-502 Gary C. Port Zachary T. Cusumano Paul R. Tumminello Michael G. Caparon SpxA1 and SpxA2 Act Coordinately To Fine-Tune Stress Responses and Virulence in <italic toggle="yes">Streptococcus pyogenes</italic>
description	ABSTRACT SpxA is a unique transcriptional regulator highly conserved among members of the phylum Firmicutes that binds RNA polymerase and can act as an antiactivator. Why some Firmicutes members have two highly similar SpxA paralogs is not understood. Here, we show that the SpxA paralogs of the pathogen Streptococcus pyogenes, SpxA1 and SpxA2, act coordinately to regulate virulence by fine-tuning toxin expression and stress resistance. Construction and analysis of mutants revealed that SpxA1− mutants were defective for growth under aerobic conditions, while SpxA2− mutants had severely attenuated responses to multiple stresses, including thermal and oxidative stresses. SpxA1− mutants had enhanced resistance to the cationic antimicrobial molecule polymyxin B, while SpxA2− mutants were more sensitive. In a murine model of soft tissue infection, a SpxA1− mutant was highly attenuated. In contrast, the highly stress-sensitive SpxA2− mutant was hypervirulent, exhibiting more extensive tissue damage and a greater bacterial burden than the wild-type strain. SpxA1− attenuation was associated with reduced expression of several toxins, including the SpeB cysteine protease. In contrast, SpxA2− hypervirulence correlated with toxin overexpression and could be suppressed to wild-type levels by deletion of speB. These data show that SpxA1 and SpxA2 have opposing roles in virulence and stress resistance, suggesting that they act coordinately to fine-tune toxin expression in response to stress. SpxA2− hypervirulence also shows that stress resistance is not always essential for S. pyogenes pathogenesis in soft tissue. IMPORTANCE For many pathogens, it is generally assumed that stress resistance is essential for pathogenesis. For Streptococcus pyogenes, environmental stress is also used as a signal to alter toxin expression. The amount of stress likely informs the bacterium of the strength of the host’s defense response, allowing it to adjust its toxin expression to produce the ideal amount of tissue damage, balancing between too little damage, which will result in its elimination, and too much damage, which will debilitate the host. Here we identify components of a genetic circuit involved in stress resistance and toxin expression that has a fine-tuning function in tissue damage. The circuit consists of two versions of the protein SpxA that regulate transcription and are highly similar but have opposing effects on the severity of soft tissue damage. These results will help us understand how virulence is fine-tuned in other pathogens that have two SpxA proteins.
format	article
author	Gary C. Port Zachary T. Cusumano Paul R. Tumminello Michael G. Caparon
author_facet	Gary C. Port Zachary T. Cusumano Paul R. Tumminello Michael G. Caparon
author_sort	Gary C. Port
title	SpxA1 and SpxA2 Act Coordinately To Fine-Tune Stress Responses and Virulence in <italic toggle="yes">Streptococcus pyogenes</italic>
title_short	SpxA1 and SpxA2 Act Coordinately To Fine-Tune Stress Responses and Virulence in <italic toggle="yes">Streptococcus pyogenes</italic>
title_full	SpxA1 and SpxA2 Act Coordinately To Fine-Tune Stress Responses and Virulence in <italic toggle="yes">Streptococcus pyogenes</italic>
title_fullStr	SpxA1 and SpxA2 Act Coordinately To Fine-Tune Stress Responses and Virulence in <italic toggle="yes">Streptococcus pyogenes</italic>
title_full_unstemmed	SpxA1 and SpxA2 Act Coordinately To Fine-Tune Stress Responses and Virulence in <italic toggle="yes">Streptococcus pyogenes</italic>
title_sort	spxa1 and spxa2 act coordinately to fine-tune stress responses and virulence in <italic toggle="yes">streptococcus pyogenes</italic>
publisher	American Society for Microbiology
publishDate	2017
url	https://doaj.org/article/7d9324830c88471984a4b367b730af2a
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SpxA1 and SpxA2 Act Coordinately To Fine-Tune Stress Responses and Virulence in <italic toggle="yes">Streptococcus pyogenes</italic>

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