The Pathogenic Fungus Cryptococcus neoformans and Its Adaptation to the Host Environment

The interaction of a pathogen with the host immune system is a complex and dynamic balance of cause and effect, action and reaction. While much research has been devoted to understanding the elements involved in these interactions, there still remains much we don't know. The research presented here has moved our understanding of these interactions forward, by identifying and then simplifying the relevant host conditions in order to examine how one particular pathogen, Cryptococcus neoformans, adapts to life within the host. This work easily falls into two sections. In the first, shorter, section, I hypothesize that the host environment is low in oxygen, and that an adaptive response to low oxygen conditions (hypoxia) is required by C. neoformans for successful growth and establishment of virulence in the mammalian host. The results of our study demonstrate that this is indeed the case, as mutants sensitive to hypoxia also demonstrate defects in virulence, and we characterize the role of the SREBP and Tco1 pathways in the hypoxia response. In the second section, which makes up the bulk of my thesis work, I examine the interaction of C. neoformans with macrophages, the immune cells that likely constitute the first line of defense in the host against cryptococcal infection. I observe that C. neoformans is able to avoid phagocytosis by these professional phagocytic cells, and examine the mechanisms through which the fungus inhibits macrophage phagocytosis, including copper homeostasis and a GATA transcription factor-regulated program