Host Response to Phenotypic Switch Variant of C. Neoformans

描述（由申请人提供）：本申请研究致病微生物如何适应和/或逃避宿主防御的毒力中的一般问题。大多数感染的特征是宿主和病原体之间的复杂关系，称为病理适应。正在研究的系统是基于新型隐球菌，这是一种人类致病真菌，是免疫功能低下患者死亡和发病的主要原因。C.在慢性感染过程中，新生儿经历了从光滑（SM）到粘液样（MC）菌落转换变体的表型转换。先前的工作已经将这种转换与包括高颅内压和在宿主中持续存在的能力在内的毒力联系起来。我们已经确定SM父节点到 高毒力MC变体与几种基因的下调有关，其中包括ALL 1和ALL 2。这些基因编码功能未知的高度同源的胞质蛋白。这些蛋白的缺失突变体，即all 1（？和all 2（1）模拟MC变体的超毒力表型。特别是1（？突变体具有惊人的表型，因为它在肺部感染中比SM亲本更具毒性，并在CNS感染模型中导致颅内压升高。最有趣的是，所有1（？表现出增强的抗应激性，表现出延长的寿命并分泌改变的多糖。由于荚膜多糖与高颅内压有关，我们现在有了ALL 1和毒力变化之间的机制联系。所有1（？表现出受损的包囊诱导，脱落质的不同多糖，并且对来自氧自由基的应激更有抗性。在这里，我们打算研究ALL 1的功能。我们的建议分为三个目标：（一）目的：研究全1（？突变体ii.）探讨ALL 1的功能关系iii.）为了阐明调控途径， 在all 1。

DESCRIPTION (provided by applicant): This application investigates a general problem in virulence of how pathogenic microbes adapt to and/or escape host defenses. Most infections are characterized by a complex relationship between the host and the pathogen referred to as pathoadaptation. The system under study is based on Cryptococcus neoformans, a human pathogenic fungus that is a major cause of mortality and morbidity in immunocompromised patients. C. neoformans undergoes phenotypic switching from a smooth (SM) to a mucoid (MC) colony switch variant during chronic infection. Prior work has associated this switch with virulence including high intracranial pressure and the ability to persist in the host. We have determined that the switch of the SM parent to the hypervirulent MC variant is associated with down-regulation of several genes, among them ALL1 and ALL2. These genes encode for highly homologous cytosolic proteins of unknown function. Deletion mutants of these proteins, namely all1(?and all2(, mimic the hypervirulent phenotype of the MC variant. Especially the all1(?mutant has a striking phenotype as it is more virulent than the SM parent in pulmonary infection and results in augmented intracranial pressure in a CNS infection model. Most interestingly, the all1(?exhibits enhanced stress resistance, manifests a prolonged life span and excretes an altered polysaccharide. Since capsular polysaccharide is implicated in high intracranial pressure we now have a mechanistic link between ALL1 and the changes in virulence. The all1(?exhibits impaired capsule induction, sheds a qualitative different polysaccharide and is more resistant to stress from oxygen radical. Here we propose to examine the function of ALL1. Our proposal is divided in three aims: I.) To investigate characteristics of the polysaccharide capsule in the all1(?mutant ii.) To explore the functional relationships of ALL1 iii.) To elucidate the regulatory pathway of ALL1.