Consequences of replicative aging in Cryptococcus neoformans

描述（由申请人提供）：新型隐球菌复制老化的后果新型隐球菌是一种主要的真菌病原体，主要在免疫功能低下的患者中引起衰弱的慢性脑膜脑炎。众所周知，这种真菌感染很难治疗，尽管进行了有效的抗真菌治疗，但病情进展的患者死亡率仍然很高。大量证据表明，病原体群体的微进化发生在慢性感染期间，并促进持续性疾病。对这种机制的有力支持来自人体、体外和动物模型数据。尽管很明显，菌株之间的微生物因素存在差异并导致毒力差异，但人们对这些因素仍然知之甚少。我们确定新型隐球菌会经历复制衰老，并且与年轻细胞相比，较老的细胞或对抗真菌治疗具有更强的抵抗力。这些可能会给它们带来体内生物学优势，并促进它们在某些条件下的选择。本申请旨在确定新型隐球菌的复制衰老是否影响慢性隐球菌病的发病机制。在第一个目标中，我们建议建立区分衰老和年轻新型隐球菌细胞的特征。在第二个目标中，我们建议确定衰老的新型隐球菌细胞在抗真菌选择压力下体内的命运。 公共卫生相关性：这项拨款提案研究了当新型隐球菌（一种可导致人类疾病的真菌）变老时会发生什么。我们将研究如何最好地区分老真菌细胞和年轻真菌细胞，以及这种真菌的自然衰老过程是否使这种真菌对治疗更具抵抗力。这可能有助于其在宿主中的选择。

DESCRIPTION (provided by applicant): Consequences of replicative aging in Cryptococcus neoformans Cryptococcus neoformans is a major fungal pathogen that causes a debilitating chronic meningoencephalitis predominantly in immunocompromised patients. This fungal infection is notoriously difficult to treat and despite effective antifungal therapy mortality can be high in patients with progressed disease. Ample of evidence suggests that microevolution of the pathogen population occurs during chronic infection and facilitates persistent disease. Strong support for such a mechanism comes from human, in vitro and animal model data. Although it is evident that microbial factors differ among strains and contribute to difference in virulence these factors are still poorly understood. We determined that C. neoformans undergoes replicative aging and that older cells or more resistant to antifungal treatment when compared to the younger cells. These could potentially give them a biological advantage in vivo and promote their selection under certain conditions. This application proposes to establish if replicative aging of C. neoformans affects the pathogenesis of chronic cryptococcosis. In the first Aim we propose to establish the characteristics that distinguish senescent from young C. neoformans cells. In the second Aim we propose to establish the fate of senescent C. neoformans cells in vivo under antifungal selection pressure. PUBLIC HEALTH RELEVANCE: This grant proposal studies what happens when Cryptococcus neoformans, a fungus that can causes disease in humans grows old. We will investigate how best to distinguish old fungal cells from young fungal cells and if this natural process of aging in this fungus makes this fungus more resistant to therapy. This may facilitate its selection in the host.