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Title: Impact of environmental adaptation in Candida albicans on fitness and immune evasion
Author: Pradhan, Arnab
ISNI:       0000 0004 7961 2527
Awarding Body: University of Aberdeen
Current Institution: University of Aberdeen
Date of Award: 2019
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Candida species are amongst the most frequent causes of life-threatening fungal infections worldwide. Current knowledge of anti-Candida immunity has been gleaned almost exclusively from studies of Candida albicans, the most commonly isolated pathogenic Candida species. It is becoming clear that C. albicans is a moving target for the immune system as it adapts to the microenvironments in human niches. To survive and grow in these niches the fungus adapts to changes in local nutrients and stress imposed by the host. This thesis addresses this adaptation and the resultant effects upon fungus-host interactions. C. albicans mounts robust oxidative stress responses in an attempt to protect itself against environmental challenges that include phagocytic attack. These responses involve the induction of CAT1, which encodes catalase, an abundant ferro-enzyme that detoxifies hydrogen peroxide. Constitutive CAT1 expression has been shown to enhance oxidative stress resistance and killing by phagocytic cells, and yet C. albicans has not evolved to express the high levels of catalase that mediate this protection. To investigate why, the fitness of isogenic barcoded C. albicans mutants expressing different levels of catalase was compared in the presence and absence of oxidative stress. As expected, C. albicans mutants overexpressing CAT1 were more resistant to high doses of oxidative stress. Also, clinical C. albicans isolates that are relatively resistant to oxidative stress generally displayed high basal CAT1 expression levels. However, in the absence of oxidative stress, CAT1 overexpression reduced the fitness of C. albicans. CAT1 overexpression was shown to perturb the expression of iron homeostasis genes, and the fitness defect was suppressible by iron supplementation. I also showed that CAT1 is not required for C. albicans virulence in murine models of systemic candidiasis. I concluded that, while catalase overexpression protects C. albicans from host-imposed stresses, it places demands on iron scavenging from the host. Changes in nutrients, thermal fluctuations and morphogenetic signals have been shown to trigger alterations in the C. albicans cell wall, which contains important immune stimulatory pathogenassociated molecular patterns (PAMPs) such as β-glucan. Exposure to host-derived lactate, for example, is known to induce β-glucan masking at the C. albicans cell surface, which attenuates the phagocytic response. Therefore, the impact of iron depletion upon C. albicans-host interactions was investigated using a combination of flow cytometry, phagocytosis assays and fluorescence and transmission electron microscopy. Iron-deprivation was found to trigger an increase in cell wall thickness and a reduction in β-glucan exposure. These cell wall changes appeared to be mediated by parallel signalling pathways: one involved the iron regulators, Ftr1 and Sef1, and the other required protein kinase A (Tpk1, Tpk2). Both pathways were essential for β-glucan masking in response to iron deprivation. These cell wall changes affected C. albicans-host interactions as they correlated with reduced fungal phagocytosis by murine bone-marrow derived macrophages (BMDMs) and less inflammatory responses from human peripheral blood mononuclear cells (PBMCs). C. albicans must also adapt to oxygen poor niches in the host, such as the gut, and hypoxia has been reported to affect the cell wall proteome. Therefore, I tested whether hypoxia affects cell wall architecture and PAMP exposure. Hypoxic C. albicans cells were found to have thinner cell walls than normoxic cells, and to expose less β-glucan at their cell surface. This hypoxia-induced β-glucan masking was dependent on mitochondrial signalling, which apparently involved the production of reactive oxygen species in the intramembrane space, and also upon downstream cAMP-PKA signalling. Hypoxia-induced β-glucan masking correlated with decreased cytokine responses from human PBMCs and reduced rates of phagocytosis by murine BMDMs. Taken together, the data suggest that C. albicans has evolved to exploit a range of host-derived signals to modulate the exposure of a major PAMP on its cell surface and thereby attempt to evade phagocytic attack. This is likely to contribute to the success of C. albicans as a commensal fungus and as an opportunistic pathogen.
Supervisor: Brown, Alistair J. P. ; Gow, Neil A. R. ; Erwig, Lars-Peter ; Netea, Mihai G. Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID:  DOI: Not available
Keywords: Candida albicans ; Fungal cell walls ; Immune system ; Fungus-host relationships