UCL logo

UCL Discovery

UCL home » Library Services » Electronic resources » UCL Discovery

Neutrophils sense microbe size and selectively release Neutrophil Extracellular Traps to control large pathogens

Branzk, HN; (2016) Neutrophils sense microbe size and selectively release Neutrophil Extracellular Traps to control large pathogens. Doctoral thesis , UCL (University College London). Green open access

[img]
Preview
Text
Thesis_Nora Branzk.pdf

Download (83MB) | Preview

Abstract

Neutrophils are innate immune phagocytes that are critical for antimicrobial defence. Neutrophils are thought to control infection by implementing a single antimicrobial program. It is unclear whether they are able to adapt their antimicrobial strategies to the different types of microbes they encounter. Neutrophil extracellular traps (NETs) are web-like structures that are composed of decondensed chromatin, decorated with neutrophil antimicrobial proteins. NETs have been shown to trap and kill a variety of microbes including parasites, fungi, bacteria and even viruses but their relevance for immune defence in vivo remained unresolved. Furthermore, it was unknown whether neutrophils regulate NET release to selectively targeted specific microbes. This work examined the role of NETs in antimicrobial defence. Specifically, we asked whether NET release is a regulated process that targets distinct sets of microbes and how regulation of NETosis was achieved. Furthermore, we examined the relevance of NETs against different microbes in vivo. Finally, we investigated which receptors were involved in triggering NET release in response to the fungus Candida albicans. Using dimorphic fungi and bacteria we found that the neutrophils regulate their antimicrobial strategies depending on the size of the microbe they encounter. Small microbes such as C. albicans yeast are phagocytosed, whereas large microbes such as C. albicans hyphae trigger NET formation. NETs were critical for the clearance of large hyphae but were dispensable against small yeast in mice. These data explain the specific susceptibility to fungal infection observed in MPO-deficient patients, whose neutrophils are defective in NET formation. Importantly, we found that phagocytosis is a negative regulator of the NETosis pathway. Sequestration of neutrophil elastase in the phagosome inhibits its translocation to the nucleus, a crucial requirement for NETosis. This strict regulation was crucial since excessive release of NET caused tissue damage and immune pathology. Furthermore, we identified a set of C. albicans cell wall mutants that failed to trigger NETosis, indicating that N- and O-linked mannosylation of cell wall proteins might be implicated in NET induction. Consistently, preliminary results suggest the involvement of TLR4 and MR in the initiation of the NETosis pathway upon stimulation with C. albicans.

Type: Thesis (Doctoral)
Title: Neutrophils sense microbe size and selectively release Neutrophil Extracellular Traps to control large pathogens
Event: UCL (University College London)
Open access status: An open access version is available from UCL Discovery
Language: English
Keywords: NETs, C. albicans, Fungi, Neutrophils, Innate immunity, Inflammation, Antimicrobial
UCL classification: UCL > Provost and Vice Provost Offices
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Medical Sciences
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Medical Sciences > Div of Infection and Immunity
URI: http://discovery.ucl.ac.uk/id/eprint/1496096
Downloads since deposit
55Downloads
Download activity - last month
Download activity - last 12 months
Downloads by country - last 12 months

Archive Staff Only

View Item View Item