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Interactions between Streptococcus pyogenes and the Human Immune System

Weineisen, Maria LU (2006) In Lund University Faculty of Medicine Doctoral Dissertation Series
Abstract
Streptococcus pyogenes is a common human pathogen causing mild infections such as tonsillitis and pharyngitis, but is also the cause of life-threatening conditions. To be able to infect the human host, S. pyogenes express different virulence factors. The surface-expressed M protein is a major virulence factor of S. pyogenes, mediating resistance to killing by human neutrophils. Results presented in this thesis show that in the presence of plasma from non-immune individuals, S. pyogenes avoids killing by human neutrophils by M protein-mediated inhibition of adhesion to the neutrophils. By comparing a wild type strain and a strain deficient in M protein-expression, the interactions between S. pyogenes and human neutrophils were studied. The... (More)
Streptococcus pyogenes is a common human pathogen causing mild infections such as tonsillitis and pharyngitis, but is also the cause of life-threatening conditions. To be able to infect the human host, S. pyogenes express different virulence factors. The surface-expressed M protein is a major virulence factor of S. pyogenes, mediating resistance to killing by human neutrophils. Results presented in this thesis show that in the presence of plasma from non-immune individuals, S. pyogenes avoids killing by human neutrophils by M protein-mediated inhibition of adhesion to the neutrophils. By comparing a wild type strain and a strain deficient in M protein-expression, the interactions between S. pyogenes and human neutrophils were studied. The interactions between S. pyogenes and human neutrophils in the presence of non-immune plasma are mediated mainly by complement components deposited on the bacterial surface and CD11b/CD18 expressed on the neutrophil surface. This interaction leads to the effective ingestion and killing of the bacteria. The activation of CD11b/CD18 leads to the activation of tyrosine kinases and the subsequent activation of the small Rho GTPase Cdc42. In blood from immune humans, S. pyogenes are opsonized and killed. In this thesis, we show that killing is mediated by Abs directed against the N-terminal part of the M protein and that these Abs activate the complement system. In the presence of serum from immune individuals, the killing of S. pyogenes is mediated through activation of the complement system by M protein-specific Abs and activation of CD11b/CD18 and Cdc42 and subsequently phagocytosis. Almost all strains of S. pyogenes bind fibrinogen (Fg) and the Fg-binding is associated with members of the M protein family. We mapped the binding of Fg to the B repeats of the M1 and M5 proteins and demonstrated that the Fg-binding is important for these bacteria to resist killing when incubated in human blood. The conditions under which the interactions between S. pyogenes and human neutrophils were investigated in the studies described above resemble the situation in bacteremia (a low multiplicity of infection, MOI, i.e. bacteria: neutrophil ratio). However, at the initial stages of infection, occurring at skin or mucosal surfaces, the bacteria to neutrophil ratio is much higher. Using two different model systems to study the interactions of S. pyogenes and phagocytes at a higher MOI, we found that this interaction is mediated by fibronectin deposited at the bacterial surface and the integrins ?5?1 and ?v?3 expressed on the phagocytes. (Less)
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author
supervisor
opponent
  • Professor Dahlgren, Claes, Avdelningen för Reumatologi och Inflammationsforskning, Göteborgs Universitet
organization
publishing date
type
Thesis
publication status
published
subject
keywords
serology, transplantation, Immunologi, serologi, virologi, mykologi, Immunology, mycology, Mikrobiologi, bakteriologi, virology, Biomedicinska vetenskaper, Neutrophils, Streptococcus pyogenes, Biomedical sciences, Phagocytosis, bacteriology, Microbiology, Integrins
in
Lund University Faculty of Medicine Doctoral Dissertation Series
pages
132 pages
publisher
Lund University, Institute of Laboratory Medicine
defense location
Rune grubb-salen, Biomedicinskt Centrum, Sölvegatan 19, Lund
defense date
2006-03-31 09:30
ISSN
1652-8220
ISBN
91-85481-63-7
language
English
LU publication?
yes
id
28f38b9a-82bd-4c6e-92e8-5dbed51bb60f (old id 546441)
date added to LUP
2007-09-20 11:33:01
date last changed
2019-05-21 21:49:36
@phdthesis{28f38b9a-82bd-4c6e-92e8-5dbed51bb60f,
  abstract     = {Streptococcus pyogenes is a common human pathogen causing mild infections such as tonsillitis and pharyngitis, but is also the cause of life-threatening conditions. To be able to infect the human host, S. pyogenes express different virulence factors. The surface-expressed M protein is a major virulence factor of S. pyogenes, mediating resistance to killing by human neutrophils. Results presented in this thesis show that in the presence of plasma from non-immune individuals, S. pyogenes avoids killing by human neutrophils by M protein-mediated inhibition of adhesion to the neutrophils. By comparing a wild type strain and a strain deficient in M protein-expression, the interactions between S. pyogenes and human neutrophils were studied. The interactions between S. pyogenes and human neutrophils in the presence of non-immune plasma are mediated mainly by complement components deposited on the bacterial surface and CD11b/CD18 expressed on the neutrophil surface. This interaction leads to the effective ingestion and killing of the bacteria. The activation of CD11b/CD18 leads to the activation of tyrosine kinases and the subsequent activation of the small Rho GTPase Cdc42. In blood from immune humans, S. pyogenes are opsonized and killed. In this thesis, we show that killing is mediated by Abs directed against the N-terminal part of the M protein and that these Abs activate the complement system. In the presence of serum from immune individuals, the killing of S. pyogenes is mediated through activation of the complement system by M protein-specific Abs and activation of CD11b/CD18 and Cdc42 and subsequently phagocytosis. Almost all strains of S. pyogenes bind fibrinogen (Fg) and the Fg-binding is associated with members of the M protein family. We mapped the binding of Fg to the B repeats of the M1 and M5 proteins and demonstrated that the Fg-binding is important for these bacteria to resist killing when incubated in human blood. The conditions under which the interactions between S. pyogenes and human neutrophils were investigated in the studies described above resemble the situation in bacteremia (a low multiplicity of infection, MOI, i.e. bacteria: neutrophil ratio). However, at the initial stages of infection, occurring at skin or mucosal surfaces, the bacteria to neutrophil ratio is much higher. Using two different model systems to study the interactions of S. pyogenes and phagocytes at a higher MOI, we found that this interaction is mediated by fibronectin deposited at the bacterial surface and the integrins ?5?1 and ?v?3 expressed on the phagocytes.},
  author       = {Weineisen, Maria},
  isbn         = {91-85481-63-7},
  issn         = {1652-8220},
  keyword      = {serology,transplantation,Immunologi,serologi,virologi,mykologi,Immunology,mycology,Mikrobiologi,bakteriologi,virology,Biomedicinska vetenskaper,Neutrophils,Streptococcus pyogenes,Biomedical sciences,Phagocytosis,bacteriology,Microbiology,Integrins},
  language     = {eng},
  pages        = {132},
  publisher    = {Lund University, Institute of Laboratory Medicine},
  school       = {Lund University},
  series       = {Lund University Faculty of Medicine Doctoral Dissertation Series},
  title        = {Interactions between Streptococcus pyogenes and the Human Immune System},
  year         = {2006},
}