The role of host variability in determining macrophage responses to cryptococcosis

Garelnabi, Mariam (2019). The role of host variability in determining macrophage responses to cryptococcosis. University of Birmingham. Ph.D.

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Abstract

Cryptoccosis remains the leading cause of fungal meningitis worldwide. Whilst one of the causative agents, C. neoformans has been described as an opportunistic pathogen of the immunocompromised, there is growing evidence of its’ abilities as a primary pathogen towards otherwise healthy individuals. This necessitates further understanding of the epidemiology and pathology to cryptococcosis in the immunocompetent patient group, as the majority of research has been conducted within the context of HIV. In this thesis, we discuss how underlying host innate immune responses vary between human hosts in response to cryptococcal disease. We present quantitative data from the in vitro challenge of monocyte-derived macrophages (MDMs) from 15 healthy individuals, showing that control of intracellular proliferation rates and yeast expulsion (vomocytosis) from macrophages vary within and between individuals. Furthermore, we show that cytokine profiles are not descriptive of this variation, and no SNPs previously associated with susceptibility to other fungal diseases were detected in this cohort. In other experiments, we show that elimination of TLR4 reduces the expulsion of cryptococci from murine macrophages. Lastly, we provide data that contributed to identifying the off-patent drug, Fendiline Hydrochloride, as a potential anticryptococcal treatment.

Type of Work:

Thesis (Doctorates > Ph.D.)

Award Type:

Doctorates > Ph.D.

Supervisor(s):