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

Research output: ThesisDoctoral Thesis (compilation)

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 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.

Details

Authors
Organisations
Research areas and keywords

Subject classification (UKÄ) – MANDATORY

  • Immunology in the medical area
  • Microbiology in the medical area

Keywords

  • Innate immunity, macrophage, Streptococcus pyogenes, IL-1beta, Nad+-glycohydrolase
Original languageEnglish
QualificationDoctor
Awarding Institution
Supervisors/Assistant supervisor
Award date2019 Oct 16
Place of PublicationLund
Publisher
  • Lund University: Faculty of Medicine
Print ISBNs978-91-7619-833-9
Publication statusPublished - 2019
Publication categoryResearch

Bibliographic note

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

Total downloads

No data available

Related research output

Elsa Westerlund, Valfridsson, C., Yi, D. X. & Jenny J. Persson, 2019 Jun 18, In : Frontiers in Immunology. 10, JUN, 1385.

Research output: Contribution to journalArticle

Hancz, D., Elsa Westerlund, Valfridsson, C., Aemero, G. M., Bastiat-Sempe, B., Orning, P., Lien, E., Wessels, M. R. & Jenny J. Persson, 2019, In : Journal of Innate Immunity.

Research output: Contribution to journalArticle

Hancz, D., Elsa Westerlund, Bastiat-Sempe, B., Sharma, O., Valfridsson, C., Meyer, L., Love, J. F., O’Seaghdha, M., Wessels, M. R. & Jenny J Persson, 2017 Jul 1, In : mBio. 8, 4, e00756-17.

Research output: Contribution to journalArticle

View all (3)