Use this URL to cite or link to this record in EThOS: https://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.787397
Title: Aspergillus nidulans and chronic granulomatous disease : exploring a unique interaction
Author: King, Jill W.
ISNI:       0000 0004 7972 5169
Awarding Body: University of Aberdeen
Current Institution: University of Aberdeen
Date of Award: 2019
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Abstract:
Background: Patients with the inherited primary immunodeficiency, chronic granulomatous disease (CGD), have the highest lifetime risk of invasive aspergillosis (IA). Aspergillus nidulans infection is unique to CGD patients and results in increased mortality compared to A. fumigatus infection. However the pathogenesis of A. nidulans infection is poorly understood. The work presented in this thesis aims to evaluate the pathogenesis of A. nidulans compared to A. fumigatus infection in CGD and determine whether immunomodulatory strategies targeting interleukin (IL)-1 impact on disease outcome. Methods: X-linked CGD and wild-type mice were infected with intra-tracheal A. fumigatus or A. nidulans conidia under anaesthesia. At set time points following infection, immune cell recruitment, pulmonary cytokine production, histopathology and fungal burden were assessed. The response to treatment with hydroxychloroquine or anakinra was similarly assessed during IA. Additional in vitro experiments using murine phagocytes were performed to determine their antifungal activity against the two Aspergillus species. Results: Significant commonality was observed between A. nidulans and A. fumigatus infection, with excessive and sustained neutrophil recruitment and IL-1? production. However, the two species induced distinct inflammatory environments, with evidence of differential cytokine profiles and divergent inflammatory macrophage, dendritic cell and eosinophil responses. The anticonidial activity of CGD phagocytes was preserved against both A. nidulans and A. fumigatus. However CGD neutrophils demonstrated impaired activity against A. nidulans hyphae. We were unable to demonstrate benefit from anakinra treatment during IA in CGD mice. However, there was evidence of benefit in hydroxychloroquine treated CGD mice during A. nidulans, but not A. fumigatus infection. Conclusions: A. nidulans and A. fumigatus induce distinct inflammatory environments in CGD mice however both infections stimulate exaggerated pulmonary IL-1 release. Modifying this excessive inflammatory response remains an attractive target for immunomodulatory therapy during IA in CGD.
Supervisor: Warris, Adilia ; Brown, Gordon Douglas Sponsor: Wellcome Trust
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID: uk.bl.ethos.787397  DOI: Not available
Keywords: Chronic granulomatous disease ; Aspergillus nidulans ; Mice
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