Dataset Information

The Secreted Virulence Factor NADase of Group A Streptococcus Inhibits P2X7 Receptor-Mediated Release of IL-1?.

ABSTRACT: The common human pathogen Group A Streptococcus (GAS) causes superficial as well as invasive, life-threatening diseases. An increase in the occurrence of invasive GAS infection by strains of the M1 and M89 serotypes has been correlated with increased expression of the genetically and functionally linked virulence factors streptolysin O (SLO) and ?-NAD+-glycohydrolase (NADase). NADase affects host cells differently depending on its location: its SLO-dependent translocation into the cytosol can lead to cell death through ?-NAD+ depletion, while extracellularly located NADase inhibits IL-1? release downstream of Nlrp3 inflammasome activation. In this study, we use a macrophage infection model to investigate the NADase-dependent inhibition of IL-1? release. We show that bacteria expressing a functional NADase evade P2X7 activation, while infection with a NADase-deficient GAS strain leads to a P2X7-mediated increase in IL-1?. Further, our data indicate that in the absence of NADase, IL-1? is released through both P2X7-dependent and -independent pathways, although the precise mechanisms of how this occur are still unclear. This study adds information about the mechanism by which NADase regulates inflammasome-dependent IL-1? release, which may in part explain why increased NADase expression correlates with bacterial virulence.

SUBMITTER: Westerlund E

PROVIDER: S-EPMC6591467 | biostudies-literature | 2019

REPOSITORIES: biostudies-literature

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Publications

The Secreted Virulence Factor NADase of Group A Streptococcus Inhibits P2X7 Receptor-Mediated Release of IL-1β.

Westerlund Elsa E Valfridsson Christine C Yi Daisy X DX Persson Jenny J JJ

Frontiers in immunology 20190618

The common human pathogen Group A Streptococcus (GAS) causes superficial as well as invasive, life-threatening diseases. An increase in the occurrence of invasive GAS infection by strains of the M1 and M89 serotypes has been correlated with increased expression of the genetically and functionally linked virulence factors streptolysin O (SLO) and β-NAD+-glycohydrolase (NADase). NADase affects host cells differently depending on its location: its SLO-dependent translocation into ...[more]

PMID: 31275321

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Project description:Group A Streptococcus (GAS) (Streptococcus pyogenes) causes more than 700 million human infections each year. The significant morbidity and mortality rates associated with GAS infections are in part a consequence of the ability of this pathogen to coordinately regulate virulence factor expression during infection. RofA-like protein IV (RivR) is a member of the Mga-like family of transcriptional regulators, and previously we reported that RivR negatively regulates transcription of the hasA and grab virulence factor-encoding genes. Here, we determined that RivR inhibits the ability of GAS to survive and to replicate in human blood. To begin to assess the biochemical basis of RivR activity, we investigated its ability to form multimers, which is a characteristic of Mga-like proteins. We found that RivR forms both dimers and a higher-molecular-mass multimer, which we hypothesize is a tetramer. As cysteine residues are known to contribute to the ability of proteins to dimerize, we created a library of expression plasmids in which each of the four cysteines in RivR was converted to serine. While the C68S RivR protein was essentially unaffected in its ability to dimerize, the C32S and C377S proteins were attenuated, while the C470S protein completely lacked the ability to dimerize. Consistent with dimerization being required for regulatory activity, the C470S RivR protein was unable to repress hasA and grab gene expression in a rivR mutant. Thus, multimer formation is a prerequisite for RivR activity, which supports recent data obtained for other Mga-like family members, suggesting a common regulatory mechanism.ImportanceThe modulation of gene transcription is key to the ability of bacterial pathogens to infect hosts to cause disease. Here, we discovered that the group A Streptococcus transcription factor RivR negatively regulates the ability of this pathogen to survive in human blood, and we also began biochemical characterization of this protein. We determined that, in order for RivR to function, it must self-associate, forming both dimers (consisting of two RivR proteins) and higher-order complexes (consisting of more than two RivR proteins). This functional requirement for RivR is shared by other regulators in the same family of proteins, suggesting a common regulatory mechanism. Insight into how these transcription factors function may facilitate the development of novel therapeutic agents targeting their activity.

Dataset Information

The Secreted Virulence Factor NADase of Group A Streptococcus Inhibits P2X7 Receptor-Mediated Release of IL-1?.

Publications

The Secreted Virulence Factor NADase of Group A <i>Streptococcus</i> Inhibits P2X7 Receptor-Mediated Release of IL-1β.

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