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Interactions between Streptococcus pyogenes and the human immune defence

Nilsson, Maria E LU (2005)
Abstract
Streptococcus pyogenes is an important human pathogen frequently colonizing the throat and skin of humans. To facilitate colonization and spread and to avoid the host immune defence, streptococci are endowed with a variety of virulence factors, two of which are investigated in this thesis namely streptolysin O (SLO) and M protein.



SLO is a secreted cytolysin that forms pores in eukaryotic membranes by binding to cholesterol. This thesis shows that SLO, via calcium and p38 MAPK, stimulates polymorphonuclear neutrophilic granulocytes (PMNs) to release the pro-inflammatory mediators heparin binding protein (HBP), LL-37, ?-defensin, and elastase. This will lead to an exaggerated immune response that may be beneficial to... (More)
Streptococcus pyogenes is an important human pathogen frequently colonizing the throat and skin of humans. To facilitate colonization and spread and to avoid the host immune defence, streptococci are endowed with a variety of virulence factors, two of which are investigated in this thesis namely streptolysin O (SLO) and M protein.



SLO is a secreted cytolysin that forms pores in eukaryotic membranes by binding to cholesterol. This thesis shows that SLO, via calcium and p38 MAPK, stimulates polymorphonuclear neutrophilic granulocytes (PMNs) to release the pro-inflammatory mediators heparin binding protein (HBP), LL-37, ?-defensin, and elastase. This will lead to an exaggerated immune response that may be beneficial to streptococci and could explain some of the symptoms of severe streptococcal infections.



M proteins form a family of membrane anchored surface proteins that project from the streptococcal surface and have been linked to the characteristic feature of S. pyogenes to escape phagocytosis. The exact mechanisms underlying this phagocytosis resistance remain unknown. In one of the papers included in this thesis, we investigated the contribution of the binding of complement regulatory proteins factor H (FH) and factor H like protein-1 (FHL-1) to M5 protein. Surprisingly, FH/FHL-1 binding affects neither complement deposition nor phagocytosis resistance. In another paper, we investigated the binding between M and M-like proteins of the M1 serotype and ?2-glycoprotein I (?2-GPI). Fragments of ?2-GPI were shown to be antibacterial, and we found that the interaction of M1 protein and protein H with full-length ?2-GPI inhibited the cleavage into potentially harmful fragments of the plasma protein. In addition, M1 protein and protein H were able to neutralize the effect of the ?2-GPI antibacterial fragments in vitro.



In immune donors, streptococci are opsonized by specific antibodies and subsequently killed. Our results show that these neutralizing antibodies are directed to the N-terminal of the M protein and that they mediated killing by complement activation. We also found that surface deposited C3b binds to complement receptor 3 (CR3) on PMNs which leads to activation of Cdc 42 and Rac 2 that starts the phagocytosis process and triggers the induction of oxidative burst. (Less)
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author
supervisor
opponent
  • Professor Potempa, Jan, Department of Microbiology, Jagellonian University, Krakow, Poland and Department of Biochemistry, U
organization
publishing date
type
Thesis
publication status
published
subject
keywords
M protein, Streptococcus pyogenes, Streptolysin O, The complement system, Neutrophils, Biomedical sciences, Biomedicinska vetenskaper, General biomedical sciences, Biomedicinska vetenskaper (allmänt), Microbiology, transplantation, Immunology, serology, mykologi, virologi, bakteriologi, Mikrobiologi, mycology, virology, Immunologi, serologi, Infections, Infektioner, Clinical biology, Klinisk biologi, bacteriology
pages
150 pages
publisher
Department of Clinical Sciences, Lund University
defense location
GK-salen, Biomedicinskt Centrum, Sölvegatan 19
defense date
2005-12-09 09:30
ISSN
1652-8220
ISBN
91-85481-13-0
language
English
LU publication?
yes
id
50c150a8-d831-4ad3-92f1-b51c7bf14a77 (old id 545777)
date added to LUP
2007-09-24 09:56:12
date last changed
2016-09-19 08:44:59
@phdthesis{50c150a8-d831-4ad3-92f1-b51c7bf14a77,
  abstract     = {Streptococcus pyogenes is an important human pathogen frequently colonizing the throat and skin of humans. To facilitate colonization and spread and to avoid the host immune defence, streptococci are endowed with a variety of virulence factors, two of which are investigated in this thesis namely streptolysin O (SLO) and M protein.<br/><br>
<br/><br>
SLO is a secreted cytolysin that forms pores in eukaryotic membranes by binding to cholesterol. This thesis shows that SLO, via calcium and p38 MAPK, stimulates polymorphonuclear neutrophilic granulocytes (PMNs) to release the pro-inflammatory mediators heparin binding protein (HBP), LL-37, ?-defensin, and elastase. This will lead to an exaggerated immune response that may be beneficial to streptococci and could explain some of the symptoms of severe streptococcal infections.<br/><br>
<br/><br>
M proteins form a family of membrane anchored surface proteins that project from the streptococcal surface and have been linked to the characteristic feature of S. pyogenes to escape phagocytosis. The exact mechanisms underlying this phagocytosis resistance remain unknown. In one of the papers included in this thesis, we investigated the contribution of the binding of complement regulatory proteins factor H (FH) and factor H like protein-1 (FHL-1) to M5 protein. Surprisingly, FH/FHL-1 binding affects neither complement deposition nor phagocytosis resistance. In another paper, we investigated the binding between M and M-like proteins of the M1 serotype and ?2-glycoprotein I (?2-GPI). Fragments of ?2-GPI were shown to be antibacterial, and we found that the interaction of M1 protein and protein H with full-length ?2-GPI inhibited the cleavage into potentially harmful fragments of the plasma protein. In addition, M1 protein and protein H were able to neutralize the effect of the ?2-GPI antibacterial fragments in vitro.<br/><br>
<br/><br>
In immune donors, streptococci are opsonized by specific antibodies and subsequently killed. Our results show that these neutralizing antibodies are directed to the N-terminal of the M protein and that they mediated killing by complement activation. We also found that surface deposited C3b binds to complement receptor 3 (CR3) on PMNs which leads to activation of Cdc 42 and Rac 2 that starts the phagocytosis process and triggers the induction of oxidative burst.},
  author       = {Nilsson, Maria E},
  isbn         = {91-85481-13-0},
  issn         = {1652-8220},
  keyword      = {M protein,Streptococcus pyogenes,Streptolysin O,The complement system,Neutrophils,Biomedical sciences,Biomedicinska vetenskaper,General biomedical sciences,Biomedicinska vetenskaper (allmänt),Microbiology,transplantation,Immunology,serology,mykologi,virologi,bakteriologi,Mikrobiologi,mycology,virology,Immunologi,serologi,Infections,Infektioner,Clinical biology,Klinisk biologi,bacteriology},
  language     = {eng},
  pages        = {150},
  publisher    = {Department of Clinical Sciences, Lund University},
  school       = {Lund University},
  title        = {Interactions between Streptococcus pyogenes and the human immune defence},
  year         = {2005},
}