- Toll-like receptor and associated regulators in pneumonia and sepsis
T. van der Poll
A.F. de Vos
- Award date
- 5 June 2015
- Number of pages
- Document type
- PhD thesis
- Faculty of Medicine (AMC-UvA)
Humanity struggles against micro-organism invasion on a daily basis. Innate immunity is part of the first line of defense when it comes to preventing infection, signaling a perceived health threat and eliminating microbes before they can cause harm. Toll-like receptors (TLRs) and other pattern recognition receptors are vital in those processes. The downside of a rigorous inflammatory response elicited by host defense is detrimental collateral tissue damage and, as a consequence thereof, dysfunction of affected organs. To regulate immune responses and thus limit unnecessary tissue destruction a crucial role is reserved for inhibitors of inflammation. This thesis aims to elucidate the role of such negative regulators and associated signaling molecules in pneumonia and sepsis caused by common human pathogens.
The role of two specific negative regulators of TLR signaling (ST2 and single immunoglobulin interleukin-1 related receptor i.e.SIGIRR) and two TLR adaptor molecules (myeloid differentiation primary response 88 i.e.MyD88 & TIR-domain-containing adapter-inducing interferon-β i.e.TRIF) in murine models of gram positive (Streptococcus pneumoniae; as a primary infection or secondary to Influenza A) and gram negative (Klebsiella pneumoniae) pneumonia and sepsis is investigated. In addition, one chapter is dedicated to the pro-inflammatory signaling property of ST2 by its ligand IL-33. The last two chapters are dedicated to human studies: one concerns inhibitory molecules of innate immunity in pulmonary tuberculosis and reports soluble (s)ST2 as a potential biomarker for tuberculosis disease activity and the other further investigates the value of sST2 as a biomarker in lung infection by measuring it in community-acquired pneumonia patients.
- Research conducted at: Universiteit van Amsterdam
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