Inhibition of Inflammasome-Dependent Interleukin 1β Production by Streptococcal NAD<sup>+</sup>-Glycohydrolase: Evidence for Extracellular Activity

ABSTRACT Group A Streptococcus (GAS) is a common human pathogen and the etiologic agent of a large number of diseases ranging from mild, self-limiting infections to invasive life-threatening conditions. Two prominent virulence factors of this bacterium are the genetically and functionally linked por...

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Autores principales:	Dóra Hancz, Elsa Westerlund, Benedicte Bastiat-Sempe, Onkar Sharma, Christine Valfridsson, Lena Meyer, John F. Love, Maghnus O’Seaghdha, Michael R. Wessels, Jenny J. Persson
Formato:	article
Lenguaje:	EN
Publicado:	American Society for Microbiology 2017
Materias:	Streptococcus pyogenes host-pathogen interactions immune regulation innate immunity Microbiology QR1-502
Acceso en línea:	https://doaj.org/article/ed60a73db88044dd80ac2bc414eea6eb
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spelling	oai:doaj.org-article:ed60a73db88044dd80ac2bc414eea6eb2021-11-15T15:51:43ZInhibition of Inflammasome-Dependent Interleukin 1β Production by Streptococcal NAD<sup>+</sup>-Glycohydrolase: Evidence for Extracellular Activity10.1128/mBio.00756-172150-7511https://doaj.org/article/ed60a73db88044dd80ac2bc414eea6eb2017-09-01T00:00:00Zhttps://journals.asm.org/doi/10.1128/mBio.00756-17https://doaj.org/toc/2150-7511ABSTRACT Group A Streptococcus (GAS) is a common human pathogen and the etiologic agent of a large number of diseases ranging from mild, self-limiting infections to invasive life-threatening conditions. Two prominent virulence factors of this bacterium are the genetically and functionally linked pore-forming toxin streptolysin O (SLO) and its cotoxin NAD+-glycohydrolase (NADase). Overexpression of these toxins has been linked to increased bacterial virulence and is correlated with invasive GAS disease. NADase can be translocated into host cells by a SLO-dependent mechanism, and cytosolic NADase has been assigned multiple properties such as protection of intracellularly located GAS bacteria and induction of host cell death through energy depletion. Here, we used a set of isogenic GAS mutants and a macrophage infection model and report that streptococcal NADase inhibits the innate immune response by decreasing inflammasome-dependent interleukin 1β (IL-1β) release from infected macrophages. Regulation of IL-1β was independent of phagocytosis and ensued also under conditions not allowing SLO-dependent translocation of NADase into the host cell cytosol. Thus, our data indicate that NADase not only acts intracellularly but also has an immune regulatory function in the extracellular niche. IMPORTANCE In the mid-1980s, the incidence and severity of invasive infections caused by serotype M1 GAS suddenly increased. The results of genomic analyses suggested that this increase was due to the spread of clonal bacterial strains and identified a recombination event leading to enhanced production of the SLO and NADase toxins in these strains. However, despite its apparent importance in GAS pathogenesis, the function of NADase remains poorly understood. In this study, we demonstrate that NADase inhibits inflammasome-dependent IL-1β release from infected macrophages. While previously described functions of NADase pertain to its role upon SLO-mediated translocation into the host cell cytosol, our data suggest that the immune regulatory function of NADase is exerted by nontranslocated enzyme, identifying a previously unrecognized extracellular niche for NADase functionality. This immune regulatory property of extracellular NADase adds another possible explanation to how increased secretion of NADase correlates with bacterial virulence.Dóra HanczElsa WesterlundBenedicte Bastiat-SempeOnkar SharmaChristine ValfridssonLena MeyerJohn F. LoveMaghnus O’SeaghdhaMichael R. WesselsJenny J. PerssonAmerican Society for MicrobiologyarticleStreptococcus pyogeneshost-pathogen interactionsimmune regulationinnate immunityMicrobiologyQR1-502ENmBio, Vol 8, Iss 4 (2017)
institution	DOAJ
collection	DOAJ
language	EN
topic	Streptococcus pyogenes host-pathogen interactions immune regulation innate immunity Microbiology QR1-502
spellingShingle	Streptococcus pyogenes host-pathogen interactions immune regulation innate immunity Microbiology QR1-502 Dóra Hancz Elsa Westerlund Benedicte Bastiat-Sempe Onkar Sharma Christine Valfridsson Lena Meyer John F. Love Maghnus O’Seaghdha Michael R. Wessels Jenny J. Persson Inhibition of Inflammasome-Dependent Interleukin 1β Production by Streptococcal NAD<sup>+</sup>-Glycohydrolase: Evidence for Extracellular Activity
description	ABSTRACT Group A Streptococcus (GAS) is a common human pathogen and the etiologic agent of a large number of diseases ranging from mild, self-limiting infections to invasive life-threatening conditions. Two prominent virulence factors of this bacterium are the genetically and functionally linked pore-forming toxin streptolysin O (SLO) and its cotoxin NAD+-glycohydrolase (NADase). Overexpression of these toxins has been linked to increased bacterial virulence and is correlated with invasive GAS disease. NADase can be translocated into host cells by a SLO-dependent mechanism, and cytosolic NADase has been assigned multiple properties such as protection of intracellularly located GAS bacteria and induction of host cell death through energy depletion. Here, we used a set of isogenic GAS mutants and a macrophage infection model and report that streptococcal NADase inhibits the innate immune response by decreasing inflammasome-dependent interleukin 1β (IL-1β) release from infected macrophages. Regulation of IL-1β was independent of phagocytosis and ensued also under conditions not allowing SLO-dependent translocation of NADase into the host cell cytosol. Thus, our data indicate that NADase not only acts intracellularly but also has an immune regulatory function in the extracellular niche. IMPORTANCE In the mid-1980s, the incidence and severity of invasive infections caused by serotype M1 GAS suddenly increased. The results of genomic analyses suggested that this increase was due to the spread of clonal bacterial strains and identified a recombination event leading to enhanced production of the SLO and NADase toxins in these strains. However, despite its apparent importance in GAS pathogenesis, the function of NADase remains poorly understood. In this study, we demonstrate that NADase inhibits inflammasome-dependent IL-1β release from infected macrophages. While previously described functions of NADase pertain to its role upon SLO-mediated translocation into the host cell cytosol, our data suggest that the immune regulatory function of NADase is exerted by nontranslocated enzyme, identifying a previously unrecognized extracellular niche for NADase functionality. This immune regulatory property of extracellular NADase adds another possible explanation to how increased secretion of NADase correlates with bacterial virulence.
format	article
author	Dóra Hancz Elsa Westerlund Benedicte Bastiat-Sempe Onkar Sharma Christine Valfridsson Lena Meyer John F. Love Maghnus O’Seaghdha Michael R. Wessels Jenny J. Persson
author_facet	Dóra Hancz Elsa Westerlund Benedicte Bastiat-Sempe Onkar Sharma Christine Valfridsson Lena Meyer John F. Love Maghnus O’Seaghdha Michael R. Wessels Jenny J. Persson
author_sort	Dóra Hancz
title	Inhibition of Inflammasome-Dependent Interleukin 1β Production by Streptococcal NAD<sup>+</sup>-Glycohydrolase: Evidence for Extracellular Activity
title_short	Inhibition of Inflammasome-Dependent Interleukin 1β Production by Streptococcal NAD<sup>+</sup>-Glycohydrolase: Evidence for Extracellular Activity
title_full	Inhibition of Inflammasome-Dependent Interleukin 1β Production by Streptococcal NAD<sup>+</sup>-Glycohydrolase: Evidence for Extracellular Activity
title_fullStr	Inhibition of Inflammasome-Dependent Interleukin 1β Production by Streptococcal NAD<sup>+</sup>-Glycohydrolase: Evidence for Extracellular Activity
title_full_unstemmed	Inhibition of Inflammasome-Dependent Interleukin 1β Production by Streptococcal NAD<sup>+</sup>-Glycohydrolase: Evidence for Extracellular Activity
title_sort	inhibition of inflammasome-dependent interleukin 1β production by streptococcal nad<sup>+</sup>-glycohydrolase: evidence for extracellular activity
publisher	American Society for Microbiology
publishDate	2017
url	https://doaj.org/article/ed60a73db88044dd80ac2bc414eea6eb
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Inhibition of Inflammasome-Dependent Interleukin 1β Production by Streptococcal NAD<sup>+</sup>-Glycohydrolase: Evidence for Extracellular Activity

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