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The Great Escape - Investigating Complement Evasion Mechanisms in Pathogenic Bacteria

Magda, Michal LU orcid (2024) In Lund University, Faculty of Medicine Doctoral Dissertation Series
Abstract
The complement system, a crucial part of the innate immune system, protects the human body during bacterial infections. Complement comprises three pathways, classical, lectin, and alternative, which activate as a protein cascade. Activation of these pathways leads to the opsonization of pathogens with C3 fragments for phagocytosis, chemotaxis of phagocytes to the infection site, and deposition of MAC to lyse the bacteria.
However, pathogens such as Acinetobacter baumannii, Klebsiella pneumoniae, and Streptococcus pyogenes have evolved sophisticated mechanisms to evade complement-mediated killing. These pathogens are responsible for life-threatening nosocomial infections, causing diseases such as pneumonia, urinary tract infections,... (More)
The complement system, a crucial part of the innate immune system, protects the human body during bacterial infections. Complement comprises three pathways, classical, lectin, and alternative, which activate as a protein cascade. Activation of these pathways leads to the opsonization of pathogens with C3 fragments for phagocytosis, chemotaxis of phagocytes to the infection site, and deposition of MAC to lyse the bacteria.
However, pathogens such as Acinetobacter baumannii, Klebsiella pneumoniae, and Streptococcus pyogenes have evolved sophisticated mechanisms to evade complement-mediated killing. These pathogens are responsible for life-threatening nosocomial infections, causing diseases such as pneumonia, urinary tract infections, bloodstream infections, skin infections, and meningitis. They produce numerous virulence factors involved in host virulence, complement resistance, environmental persistence, and antibiotic resistance. In this project, we aimed to identify their complement evasion mechanisms.
In Papers I and II, we investigated the serum resistance of Acinetobacter spp. Bacteria were significantly serum-resistant despite activation of the complement system. Some A. baumannii isolates demonstrated substantially higher virulence in the Galleria mellonella animal model and exhibited much lower MAC deposition, indicating a complement evasion mechanism. Genome sequencing highlighted possible virulence mechanisms for further study. In Paper III, we analyzed the relationship between antibiotic and complement resistance in K. pneumoniae. Colistin-resistant isolates were more virulent against G. mellonella larvae and more prone to infect mice in the pneumonia model. They also presented significantly increased complement resistance. In paper IV, we evaluated the efficacy of the fusion proteins against S. pyogenes infection. The FH6-7/hFc protein bound and displaced serum-acquired FH from the bacterial surface, increasing the complement-mediated opsonization and phagocytosis of the bacterium. When used as a therapeutic, the protein significantly increased the survival rates of mice during the sepsis model.
This dissertation emphasizes the importance of further studies on human pathogens and their still unknown complement evasion strategies. A better understanding of bacterial evasion is essential for developing new treatment options. Exploiting bacterial evasion mechanisms using fusion proteins presents a promising approach to combat various bacterial infections and suggests a potential new direction in infectious disease therapy. (Less)
Please use this url to cite or link to this publication:
author
supervisor
organization
publishing date
type
Thesis
publication status
published
subject
keywords
complement system, human pathogens, Acinetobacter baumannii, Klebsiella pneumoniae, Streptococcus pyogenes, virulence factors, antibiotic resistance, fusion protein
in
Lund University, Faculty of Medicine Doctoral Dissertation Series
issue
2024:116
pages
138 pages
publisher
Lund University, Faculty of Medicine
ISSN
1652-8220
ISBN
978-91-8021-612-8
project
Identification of novel complement evasion mechanisms developed by bacterial pathogens.
language
English
LU publication?
yes
additional info
Date: 2024-10-25 Time: 09:00 Place: Agardh föreläsningssal, CRC, Jan Waldenströms gata 35, Skånes Universitetssjukhus i Malmö. Join by Zoom: https://lu-se.zoom.us/j/69979539554 External reviewer(s) Name: Meri, Seppo Title: Professor Affiliation: Department of Bacteriology and Immunology, University of Helsinki, Finland
id
1e7ae0b3-e73b-4e24-acc0-b275340be166
date added to LUP
2024-09-26 14:58:01
date last changed
2024-10-10 16:35:45
@phdthesis{1e7ae0b3-e73b-4e24-acc0-b275340be166,
  abstract     = {{The complement system, a crucial part of the innate immune system, protects the human body during bacterial infections. Complement comprises three pathways, classical, lectin, and alternative, which activate as a protein cascade. Activation of these pathways leads to the opsonization of pathogens with C3 fragments for phagocytosis, chemotaxis of phagocytes to the infection site, and deposition of MAC to lyse the bacteria.<br/>However, pathogens such as Acinetobacter baumannii, Klebsiella pneumoniae, and Streptococcus pyogenes have evolved sophisticated mechanisms to evade complement-mediated killing. These pathogens are responsible for life-threatening nosocomial infections, causing diseases such as pneumonia, urinary tract infections, bloodstream infections, skin infections, and meningitis. They produce numerous virulence factors involved in host virulence, complement resistance, environmental persistence, and antibiotic resistance. In this project, we aimed to identify their complement evasion mechanisms.<br/>In Papers I and II, we investigated the serum resistance of Acinetobacter spp. Bacteria were significantly serum-resistant despite activation of the complement system. Some A. baumannii isolates demonstrated substantially higher virulence in the Galleria mellonella animal model and exhibited much lower MAC deposition, indicating a complement evasion mechanism. Genome sequencing highlighted possible virulence mechanisms for further study. In Paper III, we analyzed the relationship between antibiotic and complement resistance in K. pneumoniae. Colistin-resistant isolates were more virulent against G. mellonella larvae and more prone to infect mice in the pneumonia model. They also presented significantly increased complement resistance. In paper IV, we evaluated the efficacy of the fusion proteins against S. pyogenes infection. The FH6-7/hFc protein bound and displaced serum-acquired FH from the bacterial surface, increasing the complement-mediated opsonization and phagocytosis of the bacterium. When used as a therapeutic, the protein significantly increased the survival rates of mice during the sepsis model.<br/>This dissertation emphasizes the importance of further studies on human pathogens and their still unknown complement evasion strategies. A better understanding of bacterial evasion is essential for developing new treatment options. Exploiting bacterial evasion mechanisms using fusion proteins presents a promising approach to combat various bacterial infections and suggests a potential new direction in infectious disease therapy.}},
  author       = {{Magda, Michal}},
  isbn         = {{978-91-8021-612-8}},
  issn         = {{1652-8220}},
  keywords     = {{complement system; human pathogens; Acinetobacter baumannii; Klebsiella pneumoniae; Streptococcus pyogenes; virulence factors; antibiotic resistance; fusion protein}},
  language     = {{eng}},
  number       = {{2024:116}},
  publisher    = {{Lund University, Faculty of Medicine}},
  school       = {{Lund University}},
  series       = {{Lund University, Faculty of Medicine Doctoral Dissertation Series}},
  title        = {{The Great Escape - Investigating Complement Evasion Mechanisms in Pathogenic Bacteria}},
  url          = {{https://lup.lub.lu.se/search/files/195900819/Thesis_MIchal_Magda_LUCRIS.pdf}},
  year         = {{2024}},
}