Consequences of replicative aging in Cryptococcus neoformans

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性慢性脑膜脑炎。众所周知，这种真菌感染很难治疗，尽管有有效的抗真菌治疗，但病情进展的患者死亡率可能很高。大量证据表明，病原体种群的微进化发生在慢性感染期间，并促进了疾病的持续发展。人体、体外和动物模型数据有力地支持了这一机制。虽然很明显，菌株之间的微生物因素不同，并有助于不同的毒力，但这些因素仍然知之甚少。我们确定，新生C.经历了复制老化，与年轻细胞相比，较老的细胞或对抗真菌治疗更有抵抗力。这可能会使它们在体内具有生物学优势，并在某些条件下促进它们的选择。本应用旨在确定新生隐球菌的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的新生C.细胞的特征。在第二个目标中，我们提出在抗真菌选择压力下建立衰老的新生C.细胞在体内的命运。

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.