Cryptococcus neoformans Requires the ESCRT Protein Vps23 for Iron Acquisition from Heme, for Capsule Formation, and for Virulence
Cryptococcus neoformans Requires the ESCRT Protein Vps23 for Iron Acquisition from Heme, for Capsule Formation, and for Virulence
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DOI：
10.1128/iai.01037-12
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发表时间：
2013-01-01
影响因子：
3.1
通讯作者：
Kronstad, James
中科院分区：
文献类型：
--
作者：
Hu, Guanggan;Caza, Melissa;Kronstad, James
铁的利用率是新型隐球菌毒力因子产生的关键调节因子，新型隐球菌是HIV/AIDS患者真菌性脑膜脑炎的病原体。此外，铁是哺乳动物宿主中病原体增殖的必需营养素，但对攻击人类的真菌病原体的铁感测和摄取机制知之甚少。本研究采用诱变C.通过农杆菌介导的T-DNA插入对neoformans进行筛选，并筛选在血红素作为唯一铁源上生长减少的突变体。在34个突变体中，我们确定了一个子集，在ESCRT-I（内体分选复合物运输所需的）蛋白Vps 23的基因中插入，导致血红素生长缺陷，可能是由于通过内吞或从血红素铁收购的失调摄取缺陷。值得注意的是，vps 23突变体也有缺陷的阐述细胞相关的荚膜多糖，这是一个主要的毒力因子，而Vps 23的过表达导致细胞略有扩大的胶囊。这些表型反映了在vps 23突变体的隐球菌病小鼠模型中的毒力缺陷和过表达菌株的高毒力。总的来说，这些结果揭示了通过ESCRT功能在血红素摄取和胶囊形成中的重要作用，并且它们进一步加强了铁和C中毒力因子部署之间的联系。新人类
Iron availability is a key regulator of virulence factor elaboration in Cryptococcus neoformans, the causative agent of fungal meningoencephalitis in HIV/AIDS patients. In addition, iron is an essential nutrient for pathogen proliferation in mammalian hosts but little is known about the mechanisms of iron sensing and uptake in fungal pathogens that attack humans. In this study, we mutagenized C. neoformans by Agrobacterium-mediated T-DNA insertion and screened for mutants with reduced growth on heme as the sole iron source. Among 34 mutants, we identified a subset with insertions in the gene for the ESCRT-I (endosomal sorting complex required for transport) protein Vps23 that resulted in a growth defect on heme, presumably due to a defect in uptake via endocytosis or misregulation of iron acquisition from heme. Remarkably, vps23 mutants were also defective in the elaboration of the cell-associated capsular polysaccharide that is a major virulence factor, while overexpression of Vps23 resulted in cells with a slightly enlarged capsule. These phenotypes were mirrored by a virulence defect in the vps23 mutant in a mouse model of cryptococcosis and by hypervirulence of the overexpression strain. Overall, these results reveal an important role for trafficking via ESCRT functions in both heme uptake and capsule formation, and they further reinforce the connection between iron and virulence factor deployment in C. neoformans.