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Leaderless secreted peptide signaling molecule alters global gene expression and increases virulence of a human bacterial pathogen.

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Title: Leaderless secreted peptide signaling molecule alters global gene expression and increases virulence of a human bacterial pathogen.
Authors: Do, Hackwon1,2, Makthal, Nishanth1,2, Vanderwal, Arica R.1,2, Rettel, Mandy3, Savitski, Mikhail M.3, Peschek, Nikolai4, Papenfort, Kai4, Olsen, Randall J.1,2,5, Musser, James M.1,2,5, Kumaraswami, Muthiah1,2 mkumaraswami@houstonmethodist.org
Source: Proceedings of the National Academy of Sciences of the United States of America. 10/3/2017, Vol. 114 Issue 40, pE8498-E8507. 10p.
Subjects: Pathogenic bacteria, Streptococcus pyogenes, Protease inhibitors, Signal peptides, Virulence of bacteria, Gene expression in bacteria
Abstract: Successful pathogens use complex signaling mechanisms to monitor their environment and reprogram global gene expression during specific stages of infection. Group A Streptococcus (GAS) is a major human pathogen that causes significant disease burden worldwide. A secreted cysteine protease known as streptococcal pyrogenic exotoxin B (SpeB) is a key virulence factor that is produced abundantly during infection and is critical for GAS pathogenesis. Although identified nearly a century ago, the molecular basis for growth phase control of speB gene expression remains unknown. We have discovered that GAS uses a previously unknown peptide-mediated intercellular signaling system to control SpeB production, alter global gene expression, and enhance virulence. GAS produces an eight-amino acid leaderless peptide [SpeB-inducing peptide (SIP)] during high cell density and uses the secreted peptide for cell-to-cell signaling to induce population-wide speB expression. The SIP signaling pathway includes peptide secretion, reimportation into the cytosol, and interaction with the intracellular global gene regulator Regulator of Protease B (RopB), resulting in SIP-dependent modulation of DNA binding and regulatory activity of RopB. Notably, SIP signaling causes differential expression of ~14% of GAS core genes. Several genes that encode toxins and other virulence genes that enhance pathogen dissemination and infection are significantly up-regulated. Using three mouse infection models, we show that the SIP signaling pathway is active during infection and contributes significantly to GAS pathogenesis at multiple host anatomic sites. Together, our results delineate the molecular mechanisms involved in a previously undescribed virulence regulatory pathway of an important human pathogen and suggest new therapeutic strategies. [ABSTRACT FROM AUTHOR]
Copyright of Proceedings of the National Academy of Sciences of the United States of America is the property of National Academy of Sciences and its content may not be copied or emailed to multiple sites without the copyright holder's express written permission. Additionally, content may not be used with any artificial intelligence tools or machine learning technologies. However, users may print, download, or email articles for individual use. This abstract may be abridged. No warranty is given about the accuracy of the copy. Users should refer to the original published version of the material for the full abstract. (Copyright applies to all Abstracts.)
Database: Engineering Source
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  Data: Leaderless secreted peptide signaling molecule alters global gene expression and increases virulence of a human bacterial pathogen.
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  Data: <searchLink fieldCode="AR" term="%22Do%2C+Hackwon%22">Do, Hackwon</searchLink><relatesTo>1,2</relatesTo><br /><searchLink fieldCode="AR" term="%22Makthal%2C+Nishanth%22">Makthal, Nishanth</searchLink><relatesTo>1,2</relatesTo><br /><searchLink fieldCode="AR" term="%22Vanderwal%2C+Arica+R%2E%22">Vanderwal, Arica R.</searchLink><relatesTo>1,2</relatesTo><br /><searchLink fieldCode="AR" term="%22Rettel%2C+Mandy%22">Rettel, Mandy</searchLink><relatesTo>3</relatesTo><br /><searchLink fieldCode="AR" term="%22Savitski%2C+Mikhail+M%2E%22">Savitski, Mikhail M.</searchLink><relatesTo>3</relatesTo><br /><searchLink fieldCode="AR" term="%22Peschek%2C+Nikolai%22">Peschek, Nikolai</searchLink><relatesTo>4</relatesTo><br /><searchLink fieldCode="AR" term="%22Papenfort%2C+Kai%22">Papenfort, Kai</searchLink><relatesTo>4</relatesTo><br /><searchLink fieldCode="AR" term="%22Olsen%2C+Randall+J%2E%22">Olsen, Randall J.</searchLink><relatesTo>1,2,5</relatesTo><br /><searchLink fieldCode="AR" term="%22Musser%2C+James+M%2E%22">Musser, James M.</searchLink><relatesTo>1,2,5</relatesTo><br /><searchLink fieldCode="AR" term="%22Kumaraswami%2C+Muthiah%22">Kumaraswami, Muthiah</searchLink><relatesTo>1,2</relatesTo><i> mkumaraswami@houstonmethodist.org</i>
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  Data: <searchLink fieldCode="DE" term="%22Pathogenic+bacteria%22">Pathogenic bacteria</searchLink><br /><searchLink fieldCode="DE" term="%22Streptococcus+pyogenes%22">Streptococcus pyogenes</searchLink><br /><searchLink fieldCode="DE" term="%22Protease+inhibitors%22">Protease inhibitors</searchLink><br /><searchLink fieldCode="DE" term="%22Signal+peptides%22">Signal peptides</searchLink><br /><searchLink fieldCode="DE" term="%22Virulence+of+bacteria%22">Virulence of bacteria</searchLink><br /><searchLink fieldCode="DE" term="%22Gene+expression+in+bacteria%22">Gene expression in bacteria</searchLink>
– Name: Abstract
  Label: Abstract
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  Data: Successful pathogens use complex signaling mechanisms to monitor their environment and reprogram global gene expression during specific stages of infection. Group A Streptococcus (GAS) is a major human pathogen that causes significant disease burden worldwide. A secreted cysteine protease known as streptococcal pyrogenic exotoxin B (SpeB) is a key virulence factor that is produced abundantly during infection and is critical for GAS pathogenesis. Although identified nearly a century ago, the molecular basis for growth phase control of speB gene expression remains unknown. We have discovered that GAS uses a previously unknown peptide-mediated intercellular signaling system to control SpeB production, alter global gene expression, and enhance virulence. GAS produces an eight-amino acid leaderless peptide [SpeB-inducing peptide (SIP)] during high cell density and uses the secreted peptide for cell-to-cell signaling to induce population-wide speB expression. The SIP signaling pathway includes peptide secretion, reimportation into the cytosol, and interaction with the intracellular global gene regulator Regulator of Protease B (RopB), resulting in SIP-dependent modulation of DNA binding and regulatory activity of RopB. Notably, SIP signaling causes differential expression of ~14% of GAS core genes. Several genes that encode toxins and other virulence genes that enhance pathogen dissemination and infection are significantly up-regulated. Using three mouse infection models, we show that the SIP signaling pathway is active during infection and contributes significantly to GAS pathogenesis at multiple host anatomic sites. Together, our results delineate the molecular mechanisms involved in a previously undescribed virulence regulatory pathway of an important human pathogen and suggest new therapeutic strategies. [ABSTRACT FROM AUTHOR]
– Name: AbstractSuppliedCopyright
  Label:
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  Data: <i>Copyright of Proceedings of the National Academy of Sciences of the United States of America is the property of National Academy of Sciences and its content may not be copied or emailed to multiple sites without the copyright holder's express written permission. Additionally, content may not be used with any artificial intelligence tools or machine learning technologies. However, users may print, download, or email articles for individual use. This abstract may be abridged. No warranty is given about the accuracy of the copy. Users should refer to the original published version of the material for the full abstract.</i> (Copyright applies to all Abstracts.)
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        Value: 10.1073/pnas.1705972114
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        Text: English
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      – SubjectFull: Pathogenic bacteria
        Type: general
      – SubjectFull: Streptococcus pyogenes
        Type: general
      – SubjectFull: Protease inhibitors
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      – SubjectFull: Signal peptides
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      – SubjectFull: Virulence of bacteria
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      – SubjectFull: Gene expression in bacteria
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              Text: 10/3/2017
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