dc.contributor.advisor |
Hall, Christopher |
|
dc.contributor.advisor |
Astin, Jonathan |
|
dc.contributor.author |
Darroch, Hannah |
|
dc.date.accessioned |
2022-03-28T02:13:03Z |
|
dc.date.available |
2022-03-28T02:13:03Z |
|
dc.date.issued |
2021 |
en |
dc.identifier.uri |
https://hdl.handle.net/2292/58604 |
|
dc.description.abstract |
Trained immunity describes the innate immune system’s ability to ‘remember’ previous
inflammatory challenges. Training involves adaptations in innate cells and their progenitors wherein,
upon secondary exposure to inflammatory stimuli, trained cells are poised to respond more
strongly/efficiently. Stimulated haematopoietic stem and progenitor cells (HSPCs) impart a trained
phenotype to newly generated myeloid cells through supporting demand-adapted myelopoiesis. At
the time of starting this thesis, no published literature had described the contribution of neutrophils
to trained immunity. Previous work in the Hall lab has shown that neutrophils generated by one mode
of demand-adapted myelopoiesis, emergency granulopoiesis (EG), display enhanced bactericidal
activity compared to neutrophils generated at homeostasis. In light of recent advancements in the
field of trained immunity around the involvement of HSPCs, it was reasoned that infectionexperienced
HSPCs generate neutrophils with a trained phenotype. To test this hypothesis, the
conserved biology and high-resolution in vivo imaging potential of larval zebrafish was exploited.
The data presented in this thesis further demonstrates that EG-generated neutrophils display enhanced
functionality. Results show that EG-generated neutrophil enhanced bactericidal activity is nonspecific,
and that elevated reactive nitrogen species production may contribute to this phenotype.
RNA-sequencing analysis suggests that the induction of mitochondrial reactive oxygen species and
the exploitation of fatty acid catabolism are likely involved in driving the enhanced bactericidal
phenotype exhibited by EG-generated neutrophils. Furthermore, through developing a unique
allotransplant protocol, infection-experienced HSPCs were shown to generate neutrophils with
enhanced bacterial killing capacity compared to infection-naïve HSPCs. This provides the first
in vivo evidence that directly links infection-driven granulopoiesis with the generation of neutrophils
with an enhanced antibacterial phenotype. The trained immune phenotype was further explored in larval zebrafish by utilising β-glucan, a potent inducer of trained immunity, and bacterial infection to
stimulate training. Results show that training confers non-specific, long-lasting protective benefits to
larvae evident of a trained phenotype and their enhanced expression of the neutrophil-attracting
chemokine cxcl8a likely plays a protective role. Taken together, the results presented in this thesis
demonstrate that infection-driven granulopoiesis and trained immunity operate in larval zebrafish to
protect against subsequent infectious challenge providing exciting avenues for further exploration. |
|
dc.publisher |
ResearchSpace@Auckland |
en |
dc.relation.ispartof |
PhD Thesis - University of Auckland |
en |
dc.relation.isreferencedby |
UoA |
en |
dc.rights |
Items in ResearchSpace are protected by copyright, with all rights reserved, unless otherwise indicated. |
en |
dc.rights |
Items in ResearchSpace are protected by copyright, with all rights reserved, unless otherwise indicated. |
|
dc.rights.uri |
https://researchspace.auckland.ac.nz/docs/uoa-docs/rights.htm |
en |
dc.rights.uri |
http://creativecommons.org/licenses/by-nc-nd/3.0/nz/ |
|
dc.title |
Exploring the interface between trained immunity and infection-driven granulopoiesis |
|
dc.type |
Thesis |
en |
thesis.degree.discipline |
Medical and Health Science |
|
thesis.degree.grantor |
The University of Auckland |
en |
thesis.degree.level |
Doctoral |
en |
thesis.degree.name |
PhD |
en |
dc.date.updated |
2022-03-16T21:20:34Z |
|
dc.rights.holder |
Copyright: The author |
en |
dc.rights.accessrights |
http://purl.org/eprint/accessRights/OpenAccess |
en |