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CLRs and their role during Aspergillus fumigatus infection

Griffiths, James 2018. CLRs and their role during Aspergillus fumigatus infection. PhD Thesis, Cardiff University.
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Abstract

CLRs are vital for orchestrating anti-fungal immunity. These receptors are expressed on myeloid immune cells and induce robust anti-A.f. responses including phagocytosis, cytokine and chemokine release, respiratory burst, and inflammasome activation. The role of Dectin-1 has been thoroughly investigated; however, the CLRs requirement during anti-A.f. response is controversial. The impact of Dectin-2, Mcl and Mincle during anti-A.f. immunity is not well understood. A.f. is complex and poses many challenges for the immune system. PRR collaboration is likely required for A.f. clearance. Collaboration between TLRs and CLRs has been identified. Recently, the first CLR:CLR collaboration was demonstrated between Dectin-1 and Dectin-2; however, this was not in response to A.f.. The research in this thesis describes many novel interactions between CLRs and A.f. and seeks to further the understanding of the complex collaborative anti-A.f. immune response. Firstly, a novel role for NE inducing Dectin-1 Isoform A cleavage was described. This impaired A.f. recognition and the anti-A.f. response. CF patients possess high airway NE activity and experience a severe A.f. disease burden. My research suggests blocking the action of NE in CF patient’s airway may restore Dectin-1 expression and improve patient’s anti-A.f. immune response. Secondly, in vivo CLR KO and DKO models were used to elicit alveolar macrophages reliance on CLRs when generating anti-A.f. responses. My research suggests Dectin-1 might exclusively be required during early anti-A.f. responses. Unfortunately, discrepancies between the sex and microbiome of mice restricted the conclusions drawn from in vivo CLR KO and DKO A.f. infection experiments. Finally, I identified novel risk factors that can be used to stratify patients according to their susceptibility to A.f. infection. A.f. disease incidence and mortality rates are unacceptably high in immune-suppressed patients. Patients are often prophylactically treated with inadequate anti-fungal therapeutics. Stratifying patients according to their A.f. disease susceptibility would allow a personalised medicine approach and reduce unnecessary treatment.

Item Type: Thesis (PhD)
Date Type: Completion
Status: Unpublished
Schools: Medicine
Date of First Compliant Deposit: 4 September 2018
Last Modified: 03 Oct 2019 02:26
URI: http://orca.cf.ac.uk/id/eprint/114588

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