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Title: Stimulation of innate immune resistance leads to clearance of C. neoformans infection in zebrafish
Author: Kamuyango, Alfred Alinafe
ISNI:       0000 0004 7225 3429
Awarding Body: University of Sheffield
Current Institution: University of Sheffield
Date of Award: 2017
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Cryptococcus neoformans is an opportunistic pathogen and a leading cause of life-threatening fungal infections in the immunocompromised. Individuals that are at greater risk are those with defective T-cell mediated immunity such as those with HIV/AIDS. Despite treatment with anti-fungal drugs, mortality remains excessively high and patients experience serious side effects hence the need to explore new therapeutic strategies. Activation of macrophages is essential for the control of cryptococcal infection. However, in the absence of T-cell mediated immunity, activation of macrophages is disrupted and clearance of cryptococcal infection is abrogated. Herein I first report a zebrafish-C. neoformans model of infection and show that zebrafish can clear, control or fail to control cryptococcal infection. I then go on to test whether cytokines or PRR ligands are capable of stimulating innate immune resistance to C. neoformans in zebrafish. I demonstrate that concomitant injection of IFNγ with C. neoformans results in reduced fungal burden and increased fungal clearance. IFNγ increases the recruitment of phagocytes to the site of infection and enhances phagocytosis by macrophages. Macrophage deficient larvae fail to clear or suppress cryptococcal infection despite treatment with IFNγ. In addition, infected macrophages display low lysosomal pH and elevated expression of IL-1β in IFNγ-treated larvae. Although neutrophils take up the fungus, their depletion does not alter cryptococcal burden. Secondly, I demonstrate that S. aureus CWP is a potent inducer of innate defences against C. neoformans. Using chemically digested S. aureus CWP to remove wall teichoic acid or mutants that do not produce wall teichoic acid (tarO) or lipoproteins (lgt), I establish that protective effects of S. aureus CWP require wall teichoic acid but not lipoproteins. Protection by S. aureus CWP are associated with increased recruitment of macrophages but not enhanced phagocytosis or TNFα expression. This work provides new insights into cellular responses and effector molecules in the context of cryptococcal disease progression while identifying potential immunomodulatory targets.
Supervisor: Johnston, Simon Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID:  DOI: Not available