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Bacterial virulence or exorbitant host response? On innate immunity against the streptococcal M1 protein.

Persson, Sandra LU (2019) In Lund University, Faculty of Medicine Doctoral Dissertation Series 2019(105).
Abstract
Bacterial infection is inevitable throughout a lifetime. What differs between mild and
serious infections is the pathogen responsible and how the host immune system
responds to it. A fundamental role to prevent infection is a proper physical barrier such as the skin and mucosa. However, sometimes abrasions or injuries are still introduced, being potential ports of entry for pathogenic bacteria. An appropriate activation of innate immunity is necessary for bacterial elimination and wound healing. Special precautions are needed to prevent excessive host response that can result in severe tissue injury and aggravate the state of infection. This thesis has focused on studying the initial reactivity towards the streptococcal virulence... (More)
Bacterial infection is inevitable throughout a lifetime. What differs between mild and
serious infections is the pathogen responsible and how the host immune system
responds to it. A fundamental role to prevent infection is a proper physical barrier such as the skin and mucosa. However, sometimes abrasions or injuries are still introduced, being potential ports of entry for pathogenic bacteria. An appropriate activation of innate immunity is necessary for bacterial elimination and wound healing. Special precautions are needed to prevent excessive host response that can result in severe tissue injury and aggravate the state of infection. This thesis has focused on studying the initial reactivity towards the streptococcal virulence factor M1 protein, and the consequent innate host response in vitro, modelling a streptococcal skin infection. The first part of the thesis describes the vigilant activity of keratinocytes triggering PAMP-signaling when encountering the streptococcal virulence factor. This signaling pathway resulted in cytokine release, especially IL-8, enabling recruitment and activation of leukocytes. We continued by studying the delicate balance between bacterial virulence and host response to avoid excessive inflammation. The bacterial protein was not cytotoxic, however, it completely abolished any wound-healing abilities of keratinocytes in vitro. We concluded that M1 protein can aggravate the state of streptococcal skin infection, and that it is rather a bacterial virulence mechanism than due to an exorbitant host response. Moreover, we decided to investigate if CAP, a partly ionized gas with antiseptic abilities, can also modulate the inflammatory activities triggered by the streptococcal M1 protein. For the first time, we have shown that CAP is able to modulate a specific bacterial virulence factor and abolish its detrimental activities in favor of the host. Our results also show that CAP exert its antivirulence and antimicrobial functions without disturbing fundamental innate immune responses. The final part of this thesis identifies new virulence factors of Leptospira responsible for triggering massive HBP release from neutrophils. Elevated HBP levels were found in serum samples from patients suffering from Leptospirosis and could potentially be a diagnostic biomarker for the disease. In conclusion, this thesis explores new mechanisms and host responses to combat bacterial virulence important for the pathology of infectious diseases. (Less)
Please use this url to cite or link to this publication:
author
supervisor
opponent
  • Professor Sriskandan, Shiranee, Department of Medicine, Faculty of Medicine, Imperial College London
organization
publishing date
type
Thesis
publication status
published
subject
keywords
Skin infection, Streptococcus pyogenes, M1 protein, Innate Immunity, Host response, Virulence factor, Neutrophil recruitment, Heparin-binding protein (HBP), Leptospirosis
in
Lund University, Faculty of Medicine Doctoral Dissertation Series
volume
2019
issue
105
pages
76 pages
publisher
Lund University: Faculty of Medicine
defense location
Belfragesalen, BMC D15, Klinikgatan 32 i Lund
defense date
2019-10-18 09:00:00
ISSN
1652-8220
ISBN
978-91-7619-834-6
language
English
LU publication?
yes
id
2f85c10a-5182-46e2-8412-d9fa93f477c6
date added to LUP
2019-09-20 11:45:58
date last changed
2019-11-19 13:50:08
@phdthesis{2f85c10a-5182-46e2-8412-d9fa93f477c6,
  abstract     = {Bacterial infection is inevitable throughout a lifetime. What differs between mild and<br/>serious infections is the pathogen responsible and how the host immune system<br/>responds to it. A fundamental role to prevent infection is a proper physical barrier such as the skin and mucosa. However, sometimes abrasions or injuries are still introduced, being potential ports of entry for pathogenic bacteria. An appropriate activation of innate immunity is necessary for bacterial elimination and wound healing. Special precautions are needed to prevent excessive host response that can result in severe tissue injury and aggravate the state of infection. This thesis has focused on studying the initial reactivity towards the streptococcal virulence factor M1 protein, and the consequent innate host response in vitro, modelling a streptococcal skin infection. The first part of the thesis describes the vigilant activity of keratinocytes triggering PAMP-signaling when encountering the streptococcal virulence factor. This signaling pathway resulted in cytokine release, especially IL-8, enabling recruitment and activation of leukocytes. We continued by studying the delicate balance between bacterial virulence and host response to avoid excessive inflammation. The bacterial protein was not cytotoxic, however, it completely abolished any wound-healing abilities of keratinocytes in vitro. We concluded that M1 protein can aggravate the state of streptococcal skin infection, and that it is rather a bacterial virulence mechanism than due to an exorbitant host response. Moreover, we decided to investigate if CAP, a partly ionized gas with antiseptic abilities, can also modulate the inflammatory activities triggered by the streptococcal M1 protein. For the first time, we have shown that CAP is able to modulate a specific bacterial virulence factor and abolish its detrimental activities in favor of the host. Our results also show that CAP exert its antivirulence and antimicrobial functions without disturbing fundamental innate immune responses. The final part of this thesis identifies new virulence factors of Leptospira responsible for triggering massive HBP release from neutrophils. Elevated HBP levels were found in serum samples from patients suffering from Leptospirosis and could potentially be a diagnostic biomarker for the disease. In conclusion, this thesis explores new mechanisms and host responses to combat bacterial virulence important for the pathology of infectious diseases.},
  author       = {Persson, Sandra},
  isbn         = {978-91-7619-834-6},
  issn         = {1652-8220},
  language     = {eng},
  number       = {105},
  publisher    = {Lund University: Faculty of Medicine},
  school       = {Lund University},
  series       = {Lund University, Faculty of Medicine Doctoral Dissertation Series},
  title        = {Bacterial virulence or exorbitant host response? On innate immunity against the streptococcal M1 protein.},
  url          = {https://lup.lub.lu.se/search/ws/files/69738442/Bacterial_virulence_or_exorbitant_host_response.pdf},
  volume       = {2019},
  year         = {2019},
}