Old Cryptococcus neoformans cells contribute to virulence in chronic cryptococcosis.
Old Cryptococcus neoformans cells contribute to virulence in chronic cryptococcosis.
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DOI：
10.1128/mbio.00455-13
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发表时间：
2013-08-13
期刊：
影响因子：
6.4
通讯作者：
Fries BC
中科院分区：
文献类型：
--
作者：
Bouklas T;Pechuan X;Goldman DL;Edelman B;Bergman A;Fries BC
细胞年龄对毒性有影响吗？在慢性感染过程中，持续性细胞的出现对于感染的持续性至关重要，但人们对这是如何发生的知之甚少。在这里，我们首次证明了真菌病原体新隐球菌的复制年龄有助于慢性脑膜脑炎期间的持久性。年龄较大的新生C.细胞对过氧化氢应激、巨噬细胞胞内杀伤和抗真菌药物的抵抗力更强。在实验性大鼠感染和人类隐球菌病中，老细胞都有积累。数学模型支持这一概念，即较老的新生c细胞的存在来自体内的选择压力。我们认为晚期复制衰老是一种新的意想不到的毒力特征，出现在慢性真菌感染和促进持久性。针对衰老细胞的治疗干预可能有助于清除慢性感染。我们发现新隐球菌细胞的世代年龄与发病机制有关，这为真核生物发病机制的研究引入了一个新的概念。我们认为，衰老的新生C.细胞和其他真菌病原体的新特性可能有助于持久性和毒力。尽管菌株的繁殖寿命可能与毒力本身无关，但与年龄相关的恢复力以及病原体群体中单个新生C.细胞的代际年龄可能会极大地影响病原体群体的持久性，从而影响结果。
Does cell age matter in virulence? The emergence of persister cells during chronic infections is critical for persistence of infection, but little is known how this occurs. Here, we demonstrate for the first time that the replicative age of the fungal pathogen Cryptococcus neoformans contributes to persistence during chronic meningoencephalitis. Generationally older C. neoformans cells are more resistant to hydrogen peroxide stress, macrophage intracellular killing, and antifungal agents. Older cells accumulate in both experimental rat infection and in human cryptococcosis. Mathematical modeling supports the concept that the presence of older C. neoformans cells emerges from in vivo selection pressures. We propose that advanced replicative aging is a new unanticipated virulence trait that emerges during chronic fungal infection and facilitates persistence. Therapeutic interventions that target old cells could help in the clearance of chronic infections. Our findings that the generational age of Cryptococcus neoformans cells matters in pathogenesis introduces a novel concept to eukaryotic pathogenesis research. We propose that emerging properties of aging C. neoformans cells and possibly also other fungal pathogens contribute to persistence and virulence. Whereas the replicative life span of strains may not matter for virulence per se, age-related resilience and thus the generational age of individual C. neoformans cells within a pathogen population could greatly affect persistence of the pathogen population and therefore impact outcome.