Mechanisms of brain infection by the human fungal pathogen Cryptococcus neoformans

Sabiiti, Wilber (2012). Mechanisms of brain infection by the human fungal pathogen Cryptococcus neoformans. University of Birmingham. Ph.D.

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Abstract

Known for over a hundred years, the human fungal pathogen, Cryptococcus neoformans causes cryptococcosis, a life threatening disease. Infection is acquired through inhalation of spores or dried yeast cells into the lungs from which the fungus can potentially transmit to all body parts of which the brain is the most affected organ. Once in the brain, the yeast C. neoformans causes meningoencephalitis, a fatal condition even with optimal treatment. The mechanism by which C. neoformans penetrates the normally impermeable blood brain barrier (BBB) to cause brain infection is not understood. This thesis presents two aspects of investigation: 1) the extent to which binding and uptake of cryptococci by brain microvascular endothelial cells (BMEC) explains transcytosis as a mechanism for cryptococcal traversal of the BBB and 2) the relationship between Cryptococcus – macrophage interaction and Cryptococcal meningoencaphalitis (CM) disease. We show that adherence and internalization of cryptococci by brain microvascular endothelial cells is a rare event characterized by a small number of cryptococci, an indication that C. neoformans most likely uses multiple routes to traverse the BBB. Secondly, by studying clinical isolates from cerebral spinal fluid (CSF) of HIV- associated CM patients, we demonstrate that high rate of cryptococci uptake by macrophages is associated with patient fungal burden whilst the intracellular proliferation rate is inversely associated with TNF- \(\alpha\) levels in the patient CSF. Interestingly, the high uptake – high fungal burden isolates were less encapsulated but more rapid melanin formers, traits known to modulate phagocytosis and protection from host-induced oxidative stress respectively. We therefore hypothesize that highly phagocytosed C. neoformans strains use phagocytes to disseminate faster to the brain resulting in high fungal burden.

Type of Work:

Thesis (Doctorates > Ph.D.)

Award Type:

Doctorates > Ph.D.

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