Chapter 32 : Intracellular Replication and Exit Strategies

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This chapter discusses the ability of the pathogenic cryptococci to proliferate intracellularly and examines the different strategies cryptococci use to exit host cells. The intracellular location provides a dual benefit to , both in avoiding extracellular host immune mechanisms, such as complement, and in reducing exposure to antifungal agents. The establishment of different in vitro systems that utilize cell lines and the application of techniques such as live cell imaging have contributed to rapid advances in one's understanding of the molecular mechanisms influencing ability to proliferate intracellularly. Intracellular parasitism is associated with a continuous struggle between the pathogen and its host cell. Within host cells, encounters a harsh environment of reactive oxygen and nitrogen species; oxygen, nutrient, and metal ion deprivation; and low pH and high temperatures. Therefore, the yeast expresses multiple virulence factors including a capsule, melanin, and a variety of secreted enzymes that can modify the host’s defense mechanisms to achieve intracellular replication. The melanized strain 145 is more resistant to cell death caused by lymphocytes than the less melanized strain 52. Resistance to cryptococcal infection is associated with a Th1 response and the consequent phagocyte activation, whereas Th2-polarized host responses lead to inhibition of phagocyte activity and enhanced susceptibility to . Whole-genome microarray analysis has identified a large number of candidate genes that may influence proliferative capacity and revealed an unexpected role for mitochondrial genes in regulating cryptococcal hypervirulence in the Vancouver Island strains.

Citation: Voelz K, Johnston S, May R. 2011. Intracellular Replication and Exit Strategies, p 441-450. In Heitman J, Kozel T, Kwon-Chung K, Perfect J, Casadevall A (ed), . ASM Press, Washington, DC. doi: 10.1128/9781555816858.ch32

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Tumor Necrosis Factor alpha
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Intracellular proliferation of within a J774 murine macrophage. The intracellular yeast cell starts budding after 50 min and continues replication until the macrophage is filled with yeast cells after 19 h. Times are shown in hours:minutes:seconds.

Citation: Voelz K, Johnston S, May R. 2011. Intracellular Replication and Exit Strategies, p 441-450. In Heitman J, Kozel T, Kwon-Chung K, Perfect J, Casadevall A (ed), . ASM Press, Washington, DC. doi: 10.1128/9781555816858.ch32
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Image of FIGURE 2

has three strategies for escaping macrophages: (a) lysis, (b) expulsion, and (c) lateral transfer. Time lapse microscopy of J774 cells (a, b) and human primary macrophages (c). Arrows indicate intracellular cryptococci. Times are shown in hours:minutes:seconds.

Citation: Voelz K, Johnston S, May R. 2011. Intracellular Replication and Exit Strategies, p 441-450. In Heitman J, Kozel T, Kwon-Chung K, Perfect J, Casadevall A (ed), . ASM Press, Washington, DC. doi: 10.1128/9781555816858.ch32
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