Superoxide dismutase influences the virulence of Cryptococcus neoformans by affecting growth within macrophages
Superoxide dismutase influences the virulence of Cryptococcus neoformans by affecting growth within macrophages
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DOI：
10.1128/iai.71.1.173-180.2003
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发表时间：
2003-01-01
影响因子：
3.1
通讯作者：
Perfect, JR
中科院分区：
文献类型：
--
作者：
Cox, GM;Harrison, TS;Perfect, JR
超氧化物歧化酶 (SOD) 是一种将超氧自由基转化为过氧化氢和分子氧的酶，并已被证明能够通过中和宿主产生的有毒活性氧的能力来增强许多人类致病细菌的毒力。 SOD 也被推测在真菌感染的发病机制中很重要，但这种酶的作用尚未得到严格研究。为了研究 SOD 对真菌感染发病机制的贡献，我们从人类致病酵母新型隐球菌中克隆了 Cu,Zn SOD 编码基因 (SOD])，并通过定向破坏制备了突变体。 sod]突变菌株的 SOD 活性显着降低，并且在体外对活性氧更加敏感。根据小鼠吸入模型中的累积存活率测量，sod]突变体的毒性明显低于野生型菌株和两个独立的重组菌株。体外研究证实，与野生型相比，sod]菌株的生长减弱，巨噬细胞内的重组菌株产生的一氧化氮量减少。这些发现表明 (i) Cu,Zn SOD 有助于新型隐球菌的毒力，但不是致病性所必需的； (ii) sod]菌株的毒力降低可能是由于巨噬细胞内对氧自由基的敏感性增加； (iii) 新型隐球菌中的其他抗氧化防御系统可以补偿体内 Cu,Zn SOD 的损失。
Superoxide dismutase (SOD) is an enzyme that converts superoxide radicals into hydrogen peroxide and molecular oxygen and has been shown to contribute to the virulence of many human-pathogenic bacteria through its ability to neutralize toxic levels of reactive oxygen species generated by the host. SOD has also been speculated to be important in the pathogenesis of fungal infections, but the role of this enzyme has not been rigorously investigated. To examine the contribution of SOD to the pathogenesis of fungal infections, we cloned the Cu,Zn SOD-encoding gene (SOD]) from the human-pathogenic yeast Cryptococcus neoformans and made mutants via targeted disruption. The sod] mutant strains had marked decreases in SOD activity and were strikingly more susceptible to reactive oxygen species in vitro. A sod] mutant was significantly less virulent than the wild-type strain and two independent reconstituted strains, as measured by cumulative survival in the mouse inhalational model. In vitro studies established that the sod] strain had attenuated growth compared to the growth of the wild type and a reconstituted strain inside macrophages producing reduced amounts of nitric oxide. These findings demonstrate that (i) the Cu,Zn SOD contributes to virulence but is not required for pathogenicity in C. neoformans; (ii) the decreased virulence of the sod] strain may be due to increased susceptibility to oxygen radicals within macrophages; and (iii) other antioxidant defense systems in C. neoformans can compensate for the loss of the Cu,Zn SOD in vivo.