Shedding light on the circadian clock regulation of innate immunity

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dc.contributor.advisor Hall, C en
dc.contributor.advisor Cheeseman, J en Du, Yi en 2019-02-24T23:51:32Z en 2018 en
dc.identifier.uri en
dc.description.abstract The effectiveness of the innate immune system as a first line of defence against microbes depends on its ability to recognise and destroy microbial challenges. This capability is heightened in anticipation of microbial exposure, which is driven by the circadian clock – an endogenous time-keeping system that harmonises physiological responses to external conditions. The circadian clock is regulated at the molecular level by a complex network of clock proteins including Period2, that is encoded by a light-inducible gene. However, the immune cell-specific roles of circadian clock components and how they are integrated in a broader physiological context are not well understood. These questions were addressed by taking advantage of the conserved biology, genetic tractability and live imaging potential of the zebrafish model. We firstly investigated the role of light – a potent cue that synchronises the circadian rhythm to the environmental cycle (entrainment) – as an important factor in modulating innate immunity in response to acute bacterial infection in larvae. Infection studies were performed using a light entrainment protocol that was established and validated by behavioural and gene expression analyses. Under light exposure, infected larvae displayed enhanced bacterial clearance that was associated with a greater inflammatory response. This phenotype could be recapitulated in CRISPR/Cas9-generated per2-/- mutants that displayed no aberrant circadian rhythmicity. High resolution live imaging revealed neutrophils in per2-/- mutant larvae exhibited decreased bacterial killing capacity, production of reactive oxygen species, and migrating velocities. These results revealed a new role for per2 in regulating neutrophil activity via the alternative complement pathway. Genes critical for this pathway were significantly downregulated in infected per2-/- mutant larvae, relative to infected wild-type larvae. This may potentially impair the opsonic phagocytic activity of neutrophils and the production of chemotactic factors that affect their migration. Furthermore, per2 was implicated in mitochondrial ATP production, which is known to initiate neutrophil activation. Taken together, this body of work uncovered novel mechanistic insights into the role of per2 in mediating the light enhancing effect on innate immunity. It also supports the value of the zebrafish model in elucidating immune cell-specific functions of circadian clock components in an intact physiological milieu. en
dc.publisher ResearchSpace@Auckland en
dc.relation.ispartof PhD Thesis - University of Auckland en
dc.relation.isreferencedby UoA99265119907002091 en
dc.rights Items in ResearchSpace are protected by copyright, with all rights reserved, unless otherwise indicated. Previously published items are made available in accordance with the copyright policy of the publisher. en
dc.rights.uri en
dc.rights.uri en
dc.title Shedding light on the circadian clock regulation of innate immunity en
dc.type Thesis en Molecular Medicine en The University of Auckland en Doctoral en PhD en
dc.rights.holder Copyright: The author en
dc.rights.accessrights en
pubs.elements-id 763535 en Medical and Health Sciences en Medical Sciences en Molecular Medicine en
pubs.record-created-at-source-date 2019-02-25 en

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