Host Response to Phenotypic Switch Variant of C. Neoformans

描述(由申请人提供)：本申请调查致病微生物如何适应和/或逃避宿主防御的毒力方面的一般问题。大多数感染的特征是宿主和病原体之间的复杂关系，称为病原学适应。正在研究的系统是基于新生隐球菌，这是一种人类致病真菌，是免疫受损患者死亡和发病的主要原因。在慢性感染期间，新生葡萄球菌经历了从光滑(SM)菌落到粘液(MC)菌落的表型转换。先前的工作已经将这种转换与毒力联系在一起，包括高颅内压和在宿主中持续存在的能力。我们已经确定SM父节点切换到 超强毒力MC变异与几个基因的下调有关，其中包括ALL1和ALL2。这些基因编码高度同源的胞浆蛋白，功能未知。这些蛋白的缺失突变体，即ALL1(？)和ALL2()，模仿MC变异体的超强毒力表型。尤其是all1(？)突变体具有显著的表型，因为它在肺部感染中比SM亲本毒力更强，并在中枢神经系统感染模型中导致颅内压升高。最有趣的是，ALL1(？)表现出增强的抗逆性，延长了寿命，并分泌了一种改变的多糖。由于被膜多糖与高颅压有关，我们现在有了ALL1和毒力变化之间的机制联系。Al1(？)表现出被膜诱导受损，释放出一种不同性质的多糖，并且更能抵抗氧自由基的压力。在这里，我们建议研究ALL1的功能。我们的建议分为三个目标：i)目的：研究all1(？)突变株的多糖膜特性。探讨ALL1 III的功能关系。)阐明调控途径 ALL1.

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.