Identifying the mechanism of intracellular parasitism by Cryptococcus

隐球菌是一种自由生活的真菌，能够在人类和其他动物中引起致命的感染。我们目前对这种疾病的了解表明真菌孢子被吸入肺部，然后？躲起来？通过生活在一种叫做巨噬细胞的特殊类型的宿主细胞中，有时可以持续数年。虽然这种细胞会杀死大多数其他病原体，但隐球菌具有非凡的生存能力，并确实在巨噬细胞内生长。此外，我们最近发现，真菌也能够？逃跑？从宿主细胞内部通过一个新的过程反向吞噬作用？这一过程可能对病原体有利，因为它不会损害宿主细胞，因此不太可能引发强烈的炎症反应。为了更好地治疗这种致命疾病，我们需要了解真菌如何以这种方式操纵宿主细胞。因此，我们的应用程序旨在了解更多关于这种行为背后的分子过程。特别是，我们希望回答两个具体的问题：1）我们能否确定新的方法，使人类巨噬细胞可以被诱导破坏细胞内的隐球菌，从而消除潜伏感染？2)通过进化出一种改进的以这种方式操纵宿主细胞的能力，特定的隐球菌菌株对患者变得更危险的风险有多大？

Cryptococcus is a free-living fungus that is able to cause a fatal infection in humans and other animals. Our current understanding of this disease suggests that fungal spores are inhaled into the lung and then ?hide? from the immune system, sometimes for several years, by living inside a particular type of host cell called a macrophage. Although this cell would kill most other pathogens, Cryptococcus has a remarkable ability to survive and indeed grow inside macrophages. In addition, we have recently discovered that the fungus is also able to ?escape? from inside of this host cell by a novel process called ?reverse phagocytosis?. This process is likely to be advantageous to the pathogen since it does not damage the host cell and is therefore unlikely to trigger a strong inflammatory response. In order to develop better treatments for this lethal disease, we need to understand how the fungus can manipulate the host cell in this way. Our application is therefore directed at learning more about the molecular process that underlies this behaviour. In particular, we hope to answer two specific questions:1) can we identify new ways in which human macrophages can be induced to destroy intracellular cryptococci and thereby eradicate latent infections?2) how great is the risk that particular strains of Cryptococcus will become more dangerous to patients by evolving an improved ability to manipulate host cells in this way?