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On the effects of Streptococcal NAD+-glycohydrolase and Streptolysin O on macrophages

Westerlund, Elsa LU (2019) In Lund University, Faculty of Medicine Doctoral Dissertation Series 2019(104).
Abstract
Summary
The human pathogen Streptococcus pyogenes (GAS) causes both superficial infections, such as strep throat, and invasive infections, such as necrotizing fasciitis, and is responsible for about half a million deaths each year. The number of GAS infections have increased since the 1980’s, due to the emergence of a M1T1 strain that has become widely disseminated. Increased expression of Streptolysin O (SLO) and NAD+-glycohydrolase (NADase) has been correlated with the emergence of this strain. This thesis has focused on how these two virulence factors affect cytokine release from macrophages, an innate immune cell important for the host’s defense against GAS.

In Paper I we describe a novel function for NADase: inhibition... (More)
Summary
The human pathogen Streptococcus pyogenes (GAS) causes both superficial infections, such as strep throat, and invasive infections, such as necrotizing fasciitis, and is responsible for about half a million deaths each year. The number of GAS infections have increased since the 1980’s, due to the emergence of a M1T1 strain that has become widely disseminated. Increased expression of Streptolysin O (SLO) and NAD+-glycohydrolase (NADase) has been correlated with the emergence of this strain. This thesis has focused on how these two virulence factors affect cytokine release from macrophages, an innate immune cell important for the host’s defense against GAS.

In Paper I we describe a novel function for NADase: inhibition of IL-1 release after NLRP3 inflammasome activation. This inhibitory effect was mediated by extracellularly located NADase, which represents a novel functional niche for this enzyme.

In Paper II, we explore this effect further and show that NADase inhibits an unconventional IL-1 release pathway that is dependent on the P2X7 receptor and membrane permeabilization. Interestingly, we see that IL-1 release in response to GAS is independent of the pore-forming protein GSDMD.

In Paper III we show that pro-IL-1 is ubiquitinated and degraded during GAS infection. Pro-IL-1 ubiquitination requires the presence of SLO and results in heterotypic linkage types. The broad PI3K inhibitor 3-MA rescues pro-IL-1 degradation.

Paper IV focuses on NADase and the observation that NADase binds macrophages in the absence of SLO, in contrast to what has been shown previously. Recombinant NADase binds macrophages in the absence of other bacterial proteins and induces cytokine release that requires TLR4 and CD14 and is dependent on MyD88 and TRIF.
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Please use this url to cite or link to this publication:
author
supervisor
opponent
  • PhD Henry, Thomas, Centre for Infectiology Research (CIRI), Lyon, France
organization
publishing date
type
Thesis
publication status
published
subject
keywords
Innate immunity, macrophage, Streptococcus pyogenes, IL-1beta, Nad+-glycohydrolase
in
Lund University, Faculty of Medicine Doctoral Dissertation Series
volume
2019
issue
104
pages
84 pages
publisher
Lund University: Faculty of Medicine
defense location
Segerfalksalen, BMC A10, Sölvegatan 17 i Lund
defense date
2019-10-16 13:00:00
ISSN
1652-8220
ISBN
978-91-7619-833-9
language
English
LU publication?
yes
id
8ac9bf20-164a-407e-8df2-64e775c490b3
date added to LUP
2019-09-23 12:04:54
date last changed
2019-11-19 13:49:51
@phdthesis{8ac9bf20-164a-407e-8df2-64e775c490b3,
  abstract     = {Summary<br/>The human pathogen Streptococcus pyogenes (GAS) causes both superficial infections, such as strep throat, and invasive infections, such as necrotizing fasciitis, and is responsible for about half a million deaths each year. The number of GAS infections have increased since the 1980’s, due to the emergence of a M1T1 strain that has become widely disseminated. Increased expression of Streptolysin O (SLO) and NAD+-glycohydrolase (NADase) has been correlated with the emergence of this strain. This thesis has focused on how these two virulence factors affect cytokine release from macrophages, an innate immune cell important for the host’s defense against GAS. <br/><br/>In Paper I we describe a novel function for NADase: inhibition of IL-1 release after NLRP3 inflammasome activation. This inhibitory effect was mediated by extracellularly located NADase, which represents a novel functional niche for this enzyme. <br/><br/>In Paper II, we explore this effect further and show that NADase inhibits an unconventional IL-1 release pathway that is dependent on the P2X7 receptor and membrane permeabilization. Interestingly, we see that IL-1 release in response to GAS is independent of the pore-forming protein GSDMD.  <br/><br/>In Paper III we show that pro-IL-1 is ubiquitinated and degraded during GAS infection. Pro-IL-1 ubiquitination requires the presence of SLO and results in heterotypic linkage types. The broad PI3K inhibitor 3-MA rescues pro-IL-1 degradation.<br/><br/>Paper IV focuses on NADase and the observation that NADase binds macrophages in the absence of SLO, in contrast to what has been shown previously. Recombinant NADase binds macrophages in the absence of other bacterial proteins and induces cytokine release that requires TLR4 and CD14 and is dependent on MyD88 and TRIF.<br/>},
  author       = {Westerlund, Elsa},
  isbn         = {978-91-7619-833-9},
  issn         = {1652-8220},
  language     = {eng},
  number       = {104},
  publisher    = {Lund University: Faculty of Medicine},
  school       = {Lund University},
  series       = {Lund University, Faculty of Medicine Doctoral Dissertation Series},
  title        = {On the effects of Streptococcal NAD+-glycohydrolase and Streptolysin O on macrophages},
  url          = {https://lup.lub.lu.se/search/ws/files/69813679/Elsa_Westerlund_WEBB.pdf},
  volume       = {2019},
  year         = {2019},
}