Consequences of replicative aging in Cryptococcus neoformans

描述(由申请人提供)：新生隐球菌复制衰老的后果新生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。这种真菌感染是出了名的难以治疗，尽管进行了有效的抗真菌治疗，但进展性疾病患者的死亡率可能很高。大量证据表明，病原体种群的微进化发生在慢性感染期间，并促进了持续性疾病的发生。对这种机制的有力支持来自于人类、体外和动物模型数据。尽管微生物因素在不同菌株之间明显不同，并导致毒力差异，但人们对这些因素仍知之甚少。我们确定新生芽孢杆菌经历了复制衰老，与年轻细胞相比，年龄较大的细胞或更耐受抗真菌治疗。这可能会使它们在体内具有生物学优势，并在特定条件下促进它们的选择。这项应用建议确定新生隐球菌复制老化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生隐孢子虫细胞的特征。在第二个目标中，我们建议在体内建立在抗真菌选择压力下衰老的新生隐孢子虫细胞的命运。 与公共卫生相关：这项拨款提案研究了新生隐球菌衰老时会发生什么，新生隐球菌是一种可以导致人类疾病的真菌。我们将研究如何最好地区分老的真菌细胞和年轻的真菌细胞，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.