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Streptococcus pyogenes - a manipulator of human defences

Kahn, Fredrik LU (2012) In Lund University, Faculty of Medicine Doctoral Dissertation Series 2012:18.
Abstract
Streptococcus pyogenes is a major human pathogen with more than 500 000 casualties annually of which at least 163 000 are due to invasive infections. The remainder is due to post-streptococcal complications with rheu¬matic heart disease constituting the majority. S. pyogenes also causes milder infections such as skin infections and pharyngitis with an estimation of more than 700 million cases each year. The mechanisms underlying the development of serious invasive infection are not yet fully understood.

S. pyogenes has developed multiple strategies for evading or manipulating the host defence systems to promote its own survival. A major virulence determinant of S. pyogenes is the cell surface attached M protein. It has previously... (More)
Streptococcus pyogenes is a major human pathogen with more than 500 000 casualties annually of which at least 163 000 are due to invasive infections. The remainder is due to post-streptococcal complications with rheu¬matic heart disease constituting the majority. S. pyogenes also causes milder infections such as skin infections and pharyngitis with an estimation of more than 700 million cases each year. The mechanisms underlying the development of serious invasive infection are not yet fully understood.

S. pyogenes has developed multiple strategies for evading or manipulating the host defence systems to promote its own survival. A major virulence determinant of S. pyogenes is the cell surface attached M protein. It has previously been shown that M proteins of certain serotypes form complexes with fibrinogen and that these can elicit a pathological response, which may contribute to the massive vascular leakage present in streptococ¬cal toxic shock (STSS). This thesis demonstrates that preformed antibodies against certain epitopes on the M protein contribute to triggering the neutrophils to secrete heparin binding protein, a potent inducer of vascular leakage. This might explain the inter-individual susceptibility in the development of STSS.

Platelets and neutrophils can form complexes through a mutual interaction with each other. Such complexes have been implicated in the pathophysiology of many diseases (e.g. sepsis, acute lung injury, atherosclerosis) and it has previously been shown that neutrophils in such complexes are more active. In this thesis M protein was shown to generate platelet-neutrophil complexes. The formation of platelet-neutrophil complexes was dependent on specific IgG directed against the central domain of M protein. Such antibodies together with fibrinogen and M protein induce the formation of platelet-neutrophil complexes. This is another example of how M protein in the presence of specific antibodies elicits a more inflammatory phenotype.

The contribution of platelets to the pathogenesis of a bacterial infection was studied in a murine model of invasive S. pyogenes. S. pyogenes infection gave rise to a profound thrombocytopenia and concomitant rise in circulating platelet-neutrophil complexes. Reduction of the number of platelets with an antibody prior to infec¬tion resulted in diminished dissemination of bacteria to the spleen. The animals also decreased significantly less in weight and had a diminished acute phase response implying platelet participation in bacterial spreading and to the pathogenesis of this infection.

In clinical infections S. pyogenes seldom causes an abscess outside the pharyngeal tract. This thesis reports a rare case of an axillary abscess due to S. pyogenes. Since the patient already was on treatment with antibiotics cultures were negative. Nevertheless determination of the aetiological agent as well as typing could be achieved using molecular biology techniques from abscess material. Serology indicated that the bacterium had expressed pro¬coagulant factors. The expression of such factors could have contributed to the development of venous throm¬bosis, which was a complication of abscess formation in this patient.

Taken together this thesis demonstrates how S. pyogenes promotes its own survival by manipulating different host defence systems. (Less)
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author
supervisor
opponent
  • Treutiger, Carl Johan, Karolinska Institutet Institutionen för medicin, Huddinge (MedH), H7 Karolinska Universitetssjukhuset Huddinge
organization
publishing date
type
Thesis
publication status
published
subject
keywords
Streptococcus pyogenes, M protein, neutrophils, platelets, platelet-neutrophil complexes, fibrinogen, IgG, abscess, venous thrombosis, heparin binding protein, thrombocytopenia
in
Lund University, Faculty of Medicine Doctoral Dissertation Series
volume
2012:18
pages
172 pages
publisher
Division of Infection Medicine
defense location
Belfragesalen , D15, BMC
defense date
2012-03-09 09:15
ISSN
1652-8220
ISBN
978-91-86871-80-2
language
English
LU publication?
yes
id
2487940a-53f3-4f24-a467-7aa25d4c22b3 (old id 2343029)
date added to LUP
2012-02-17 11:38:54
date last changed
2016-09-19 08:44:49
@phdthesis{2487940a-53f3-4f24-a467-7aa25d4c22b3,
  abstract     = {Streptococcus pyogenes is a major human pathogen with more than 500 000 casualties annually of which at least 163 000 are due to invasive infections. The remainder is due to post-streptococcal complications with rheu¬matic heart disease constituting the majority. S. pyogenes also causes milder infections such as skin infections and pharyngitis with an estimation of more than 700 million cases each year. The mechanisms underlying the development of serious invasive infection are not yet fully understood. <br/><br>
S. pyogenes has developed multiple strategies for evading or manipulating the host defence systems to promote its own survival. A major virulence determinant of S. pyogenes is the cell surface attached M protein. It has previously been shown that M proteins of certain serotypes form complexes with fibrinogen and that these can elicit a pathological response, which may contribute to the massive vascular leakage present in streptococ¬cal toxic shock (STSS). This thesis demonstrates that preformed antibodies against certain epitopes on the M protein contribute to triggering the neutrophils to secrete heparin binding protein, a potent inducer of vascular leakage. This might explain the inter-individual susceptibility in the development of STSS. <br/><br>
Platelets and neutrophils can form complexes through a mutual interaction with each other. Such complexes have been implicated in the pathophysiology of many diseases (e.g. sepsis, acute lung injury, atherosclerosis) and it has previously been shown that neutrophils in such complexes are more active. In this thesis M protein was shown to generate platelet-neutrophil complexes. The formation of platelet-neutrophil complexes was dependent on specific IgG directed against the central domain of M protein. Such antibodies together with fibrinogen and M protein induce the formation of platelet-neutrophil complexes. This is another example of how M protein in the presence of specific antibodies elicits a more inflammatory phenotype. <br/><br>
The contribution of platelets to the pathogenesis of a bacterial infection was studied in a murine model of invasive S. pyogenes. S. pyogenes infection gave rise to a profound thrombocytopenia and concomitant rise in circulating platelet-neutrophil complexes. Reduction of the number of platelets with an antibody prior to infec¬tion resulted in diminished dissemination of bacteria to the spleen. The animals also decreased significantly less in weight and had a diminished acute phase response implying platelet participation in bacterial spreading and to the pathogenesis of this infection. <br/><br>
In clinical infections S. pyogenes seldom causes an abscess outside the pharyngeal tract. This thesis reports a rare case of an axillary abscess due to S. pyogenes. Since the patient already was on treatment with antibiotics cultures were negative. Nevertheless determination of the aetiological agent as well as typing could be achieved using molecular biology techniques from abscess material. Serology indicated that the bacterium had expressed pro¬coagulant factors. The expression of such factors could have contributed to the development of venous throm¬bosis, which was a complication of abscess formation in this patient. <br/><br>
Taken together this thesis demonstrates how S. pyogenes promotes its own survival by manipulating different host defence systems.},
  author       = {Kahn, Fredrik},
  isbn         = {978-91-86871-80-2},
  issn         = {1652-8220},
  keyword      = {Streptococcus pyogenes,M protein,neutrophils,platelets,platelet-neutrophil complexes,fibrinogen,IgG,abscess,venous thrombosis,heparin binding protein,thrombocytopenia},
  language     = {eng},
  pages        = {172},
  publisher    = {Division of Infection Medicine},
  school       = {Lund University},
  series       = {Lund University, Faculty of Medicine Doctoral Dissertation Series},
  title        = {Streptococcus pyogenes - a manipulator of human defences},
  volume       = {2012:18},
  year         = {2012},
}