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Unraveling the immune response in sepsis and meningitis. Diagnostic and therapeutic approaches.

Fisher, Jane LU (2020) In Lund University, Faculty of Medicine Doctoral Dissertation Series
Abstract
Severe infections continue to constitute a large burden, with high mortality and risk of sequelae. Sepsis is a dysregulated host response to an infection that causes life threatening organ damage. Meningitis is a severe infection of the brain that often leads to sepsis and death or lasting neurological damage. The host response is often responsible for more damage than the pathogen itself. This thesis focuses on two components of the host response. The first is the endothelial glycocalyx, a complex matrix of glycans and proteins that modulates blood vessel function. The second are neutrophil extracellular traps (NETs), which are large structures composed of DNA and granule proteins that are released from neutrophils in response to... (More)
Severe infections continue to constitute a large burden, with high mortality and risk of sequelae. Sepsis is a dysregulated host response to an infection that causes life threatening organ damage. Meningitis is a severe infection of the brain that often leads to sepsis and death or lasting neurological damage. The host response is often responsible for more damage than the pathogen itself. This thesis focuses on two components of the host response. The first is the endothelial glycocalyx, a complex matrix of glycans and proteins that modulates blood vessel function. The second are neutrophil extracellular traps (NETs), which are large structures composed of DNA and granule proteins that are released from neutrophils in response to bacteria. The aim of this thesis was to explore diagnostic and therapeutic aspects of these components of the host immune response during sepsis and bacterial meningitis.
Translational research methods were used to find solutions to this clinical problem. An observational cohort study revealed that plasma glypicans, a component of the glycocalyx, are elevated in sepsis before the onset of organ dysfunction. A small cohort study also revealed that cerebrospinal fluid (CSF) NETs are elevated in bacterial meningitis. CSF NETs were also present to a great extent in a cohort of patients neurosurgically treated with external ventricular drains, but were not significantly elevated in those who developed infections as a result of the procedure. NETs were also present in the CSF in a rat model of bacterial meningitis and their removal using DNase increased bacterial killing. Glymphatic fluid distribution in the brain was disrupted rats with bacterial meningitis and partially restored after treatment with DNase. A second rat model was used to test and validate a new scoring system to quantify neurologic outcomes in experimental meningitis.
In this thesis work, glypicans were identified as a marker of endothelial damage in sepsis and CSF NETs were identified as a potential biomarker and therapeutic target in bacterial meningitis. Disruption of NETs by DNase should be explored further as a therapeutic in bacterial meningitis. A neurologic scoring system was established for testing of novel adjuvant therapies, such as DNase, in rat models of bacterial meningitis in the future. (Less)
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author
supervisor
opponent
  • professor Ă–stergaard Andersen, Christian, Copenhagen University Hosptial Hvidovre
organization
publishing date
type
Thesis
publication status
published
subject
keywords
meningtis, sepsis, neutrophil extracellular traps (NETs), glymphatic system, DNase, pneumococci
in
Lund University, Faculty of Medicine Doctoral Dissertation Series
issue
2020:86
pages
70 pages
publisher
Lund University, Faculty of Medicine
defense location
Belfragesalen, BMC D15, Klinikgatan 32 i Lund
defense date
2020-09-04 13:00:00
ISSN
1652-8220
ISBN
978-91-7619-948-0
language
English
LU publication?
yes
id
d44f0c7b-5fc6-4f65-96b0-1875e87a4590
date added to LUP
2020-08-14 10:19:46
date last changed
2020-08-18 13:15:08
@phdthesis{d44f0c7b-5fc6-4f65-96b0-1875e87a4590,
  abstract     = {Severe infections continue to constitute a large burden, with high mortality and risk of sequelae. Sepsis is a dysregulated host response to an infection that causes life threatening organ damage. Meningitis is a severe infection of the brain that often leads to sepsis and death or lasting neurological damage. The host response is often responsible for more damage than the pathogen itself. This thesis focuses on two components of the host response. The first is the endothelial glycocalyx, a complex matrix of glycans and proteins that modulates blood vessel function. The second are neutrophil extracellular traps (NETs), which are large structures composed of DNA and granule proteins that are released from neutrophils in response to bacteria. The aim of this thesis was to explore diagnostic and therapeutic aspects of these components of the host immune response during sepsis and bacterial meningitis.<br/>Translational research methods were used to find solutions to this clinical problem. An observational cohort study revealed that plasma glypicans, a component of the glycocalyx, are elevated in sepsis before the onset of organ dysfunction. A small cohort study also revealed that cerebrospinal fluid (CSF) NETs are elevated in bacterial meningitis. CSF NETs were also present to a great extent in a cohort of patients neurosurgically treated with external ventricular drains, but were not significantly elevated in those who developed infections as a result of the procedure. NETs were also present in the CSF in a rat model of bacterial meningitis and their removal using DNase increased bacterial killing. Glymphatic fluid distribution in the brain was disrupted rats with bacterial meningitis and partially restored after treatment with DNase. A second rat model was used to test and validate a new scoring system to quantify neurologic outcomes in experimental meningitis. <br/>In this thesis work, glypicans were identified as a marker of endothelial damage in sepsis and CSF NETs were identified as a potential biomarker and therapeutic target in bacterial meningitis. Disruption of NETs by DNase should be explored further as a therapeutic in bacterial meningitis. A neurologic scoring system was established for testing of novel adjuvant therapies, such as DNase, in rat models of bacterial meningitis in the future.},
  author       = {Fisher, Jane},
  isbn         = {978-91-7619-948-0},
  issn         = {1652-8220},
  language     = {eng},
  number       = {2020:86},
  publisher    = {Lund University, Faculty of Medicine},
  school       = {Lund University},
  series       = {Lund University, Faculty of Medicine Doctoral Dissertation Series},
  title        = {Unraveling the immune response in sepsis and meningitis. Diagnostic and therapeutic approaches.},
  url          = {https://lup.lub.lu.se/search/ws/files/82661940/Jane_Fisher_thesis_e_nailing_copy.pdf},
  year         = {2020},
}