Host Response to Phenotypic Switch Variant of C. Neoformans

描述（由申请人提供）：本申请研究病原微生物如何适应和/或逃避宿主防御的毒力的一般问题。大多数感染的特点是宿主和病原体之间的复杂关系，称为病原体适应。正在研究的系统是基于新型隐球菌，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。在慢性感染期间，新生C.经历了从光滑（SM）到黏液（MC）集落转换的表型转换。先前的工作已经将这种转换与毒力联系起来，包括高颅内压和在宿主体内持续存在的能力。我们已经确定将SM父类切换到

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.