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Inhibition of inflammasome-dependent interleukin 1β production by streptococcal NAD+-glycohydrolase : Evidence for extracellular activity

Hancz, Dóra LU ; Westerlund, Elsa LU ; Bastiat-Sempe, Benedicte ; Sharma, Onkar ; Valfridsson, Christine LU ; Meyer, Lena LU ; Love, John F. ; O’Seaghdha, Maghnus ; Wessels, Michael R and Persson, Jenny J LU (2017) In mBio 8(4).
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... (More)

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.

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author
; ; ; ; ; ; ; ; and
organization
publishing date
type
Contribution to journal
publication status
published
subject
keywords
Host-pathogen interactions, Immune regulation, Innate immunity, Streptococcus pyogenes
in
mBio
volume
8
issue
4
article number
e00756-17
publisher
American Society for Microbiology
external identifiers
  • pmid:28720729
  • wos:000409384300035
  • scopus:85029072155
ISSN
2161-2129
DOI
10.1128/mBio.00756-17
project
On the effects of Streptococcal NAD+-glycohydrolase and Streptolysin O on macrophages
language
English
LU publication?
yes
id
457a2e22-43db-4602-a9e7-63e236bbb220
date added to LUP
2017-09-27 12:52:16
date last changed
2024-01-14 05:43:30
@article{457a2e22-43db-4602-a9e7-63e236bbb220,
  abstract     = {{<p>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.</p>}},
  author       = {{Hancz, Dóra and Westerlund, Elsa and Bastiat-Sempe, Benedicte and Sharma, Onkar and Valfridsson, Christine and Meyer, Lena and Love, John F. and O’Seaghdha, Maghnus and Wessels, Michael R and Persson, Jenny J}},
  issn         = {{2161-2129}},
  keywords     = {{Host-pathogen interactions; Immune regulation; Innate immunity; Streptococcus pyogenes}},
  language     = {{eng}},
  month        = {{07}},
  number       = {{4}},
  publisher    = {{American Society for Microbiology}},
  series       = {{mBio}},
  title        = {{Inhibition of inflammasome-dependent interleukin 1β production by streptococcal NAD<sup>+</sup>-glycohydrolase : Evidence for extracellular activity}},
  url          = {{http://dx.doi.org/10.1128/mBio.00756-17}},
  doi          = {{10.1128/mBio.00756-17}},
  volume       = {{8}},
  year         = {{2017}},
}