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

Elsa Westerlund

Forskningsoutput: AvhandlingDoktorsavhandling (sammanläggning)

102 Nedladdningar (Pure)


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.
Tilldelande institution
  • Institutionen för experimentell medicinsk vetenskap
  • Persson, Jenny J, handledare
  • Herwald, Heiko, Biträdande handledare
Tilldelningsdatum2019 okt 16
Tryckta ISBN978-91-7619-833-9
StatusPublished - 2019

Bibliografisk information

Defence details
Date: 2019-10-16
Time: 13:00
Place: Segerfalksalen, BMC A10, Sölvegatan 17 i Lund
External reviewer(s)
Name: Henry, Thomas
Title: PhD
Affiliation: Centre for Infectiology Research (CIRI), Lyon, France

Ämnesklassifikation (UKÄ)

  • Immunologi inom det medicinska området
  • Mikrobiologi inom det medicinska området


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