Hoving, Dennis;
(2022)
Characterisation of innate immune dysfunction in fungal sepsis.
Doctoral thesis (Ph.D), UCL (University College London).
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Abstract
Sepsis is a complex and severe pathological condition that is characterized by hyper-inflammation followed by leukocyte dysfunction and excessive tissue injury. The mechanisms controlling immune dysregulation remain poorly understood. In this thesis, we show that fungal capture in spleen promotes inflammation and DAMPs-mediated immune dysfunction during systemic candidiasis. We identify the molecules and cellular players and define the order of events that link immune dysfunction between lymphocytes and neutrophils. SIGNR1+ marginal zone macrophages (MZMΦs) capture Candida albicans (C. albicans) and enable fungal colonization of the spleen marginal zone (MZ), triggering aberrant lymphocyte death and release of cell-free chromatin, that synergizes with fungal hyphae to stimulate G-CSF production by CD169+ marginal metallophilic macrophages (MMMΦs). G-CSF and extracellular chromatin selectively reduce the lifespan of mature Ly6Ghigh neutrophils, leading to severe neutropenia. ROS-deficient immature Ly6Glow neutrophils are mobilised and become the predominant peripheral neutrophil population, causing impaired fungal clearance and severe pathology. SIGNR1-blockade effectively limits fungal colonization in the MZ and increases survival. Similarly, T cell- deficiency or neutralization of G-CSF, chromatin or histones consistently reduces inflammation, neutrophil dysfunction and pathology. The release of cell-free actin by dying splenocytes and tissue damage further enhances pathology by interfering with extracellular chromatin clearance. These findings demonstrate that PAMPs and DAMPs mediate inflammation and neutrophil dysregulation, causing a detrimental positive feedback-loop that impairs fungal clearance and increases sepsis pathology.
| Type: | Thesis (Doctoral) |
|---|---|
| Qualification: | Ph.D |
| Title: | Characterisation of innate immune dysfunction in fungal sepsis |
| Open access status: | An open access version is available from UCL Discovery |
| Language: | English |
| Additional information: | Copyright © The Author 2022. Original content in this thesis is licensed under the terms of the Creative Commons Attribution-NonCommercial 4.0 International (CC BY-NC 4.0) Licence (https://creativecommons.org/licenses/by-nc/4.0/). Any third-party copyright material present remains the property of its respective owner(s) and is licensed under its existing terms. Access may initially be restricted at the author’s request. |
| UCL classification: | UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Life Sciences UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Life Sciences > Div of Biosciences UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences UCL |
| URI: | https://discovery.ucl.ac.uk/id/eprint/10143870 |
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