Exploring differences in the immune response triggered by clinically relevant Candida spp.

Matos Da Fonseca, Diogo 2020. Exploring differences in the immune response triggered by clinically relevant Candida spp. PhD Thesis, Cardiff University. Item availability restricted.

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Abstract

Systemic candidiasis is a life-threatening disease that affects ~750,000 people every year and has unacceptably high mortality rates due to a lack of efficient therapeutics. C. albicansis the most common and virulent agent of systemic candidiasis, whereasless virulent Candida spp. such as C. parapsilosis are more easily cleared by the host and thus have a lower incidence in comparison with C. albicans. Here, through comparative transcriptomic analysis, I sought to identify differences in the immune response triggered by C. albicans and C. parapsilosis, in order to validate C. parapsilosis-specific targets for immune modulation during C. albicansinfections. This was conducted to assess the impact of the identified targets in promoting C. albicans clearance and to determine their potential as immunotherapies for C. albicans-induced systemic candidiasis. Strikingly, I found that the C. parapsilosis-triggered macrophage immune response is dominated by the type I IFN signalling pathway, with IFN-b standing as the top upstream activator of this pathway. In vitro studies presented here reveal that IFN-b boosts the candidacidal activity of BMDMs towards C. albicans via a mechanism independent of ROS, NO and conventional AMPs. In vivo results indicate that administration of IFN-b has a negative effect on mice survival during C. albicans challenge. However, reduced kidney fungal burden was observed in mice injected with a high dose of IFN-b that survived the infection. Preliminary in vivo experiments revealed that administration of hetIL-15, a type I IFN-inducible cytokine complex, promotes splenic lymphocyte proliferation in C. albicansinjected mice, with a significant expansion of granzyme B-producing NK cell populations, and IFN-γ- and granzyme B-producing CD8+ T cells. C. albicans has been previously reported to inhibit macrophage IL-27 production, another type I IFN-inducible cytokine. I uncovered here that IL-27 inhibition is triggered by a soluble mediator, secreted during the C. albicans morphotypical transition to true hyphae. Moreover, I have also discovered a novel b-glucandriven mechanism of IL-27 inhibition dependent on Dectin-1 signalling. However, it is still unclear whether C. albicans uses this mechanism to inhibit IL-27 production. This thesis presents the first comparative analysis of the macrophage immune response triggered by C.albicans and C. parapsilosis, and the collective results displayed here can be further explored to help devising new therapeutic approaches for treatment of life-threatening systemic candidiasis.

Item Type:	Thesis (PhD)
Date Type:	Completion
Status:	Unpublished
Schools:	Medicine
Date of First Compliant Deposit:	6 November 2020
Last Modified:	08 Aug 2022 15:06
URI:	https://orca.cardiff.ac.uk/id/eprint/136149

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