Year: 2016
Type: dissertation
Abstract: Cryptococcus neoformans (C.neo) is a common monomorphic environmental yeast and opportunistic fungal pathogen that infects over 1 million people per year and causes over 680,000 deaths globally. This dissertation investigates how both C.neo virulence factors and host factors can modulate the afferent immune response, and under what circumstances these factors impact the developing efferent immune response. The overarching hypothesis is that crosstalk between host defense signals and fungal factors during the afferent immune response to C.neo by modulating dendritic cell (DC) activation and/or polarization directly impacts the developing adaptive response to become either protective or non-protective. This dissertation will primarily focus on the roles of specific cryptococcal factor Ssa1 on the microbial side, and the cytokine TNFα on the host side, to gain better insights on the mechanisms by which hosts can develop protective responses. We found that the cryptococcal virulence factor Ssa1 is capable of promoting macrophage alternative activation, but has no impact on DC activation. This results in a unique immunophenotype in the C.neo strain deficient in Ssa1 where macrophages are classically activated during the afferent immune response, but DCs remain alternatively activated regardless of the presence of Ssa1, thus priming non-protective immune responses. Conversely, we found that host production of TNFα during the afferent phase of the immune response to C.neo determines whether DCs are classically activated (with TNFα) or alternatively activated (without TNFα), and thus whether protective Th1 or non-protective Th2 immune responses develop, respectively. Furthermore, TNFα induces epigenetic modifications to DCs, epigenetically stabilizing classical activation genes via the activating modification histone 3 lysine 4 trimethylation through the action of the histone methyltransferase MLL1. This occurs both in pulmonary DCs already present and in DC precursors within the bone marrow. This thesis shows that while the afferent immune response can dramatically and permanently affect the developing efferent immune response to C.neo, as in afferent phase TNFα depletion, perturbations to the afferent response do not necessarily result in concomitant efferent changes, as in the loss of cryptococcal virulence gene Ssa1.
Author: Alison J. Eastman
Language: English
Subfield: Epidemiology
Field: Medicine
Domain: Health Sciences
Open Access status: green
OpenAlex ID: W2746520693