Saikia Sanjay, Oliveira Debora, Hu Guanggan, Kronstad James
Michael Smith Laboratories, Department of Microbiology and Immunology, and Faculty of Land and Food Systems, The University of British Columbia, Vancouver, British Columbia, Canada.
Infect Immun. 2014 Feb;82(2):839-50. doi: 10.1128/IAI.01357-13. Epub 2013 Dec 9.
Iron acquisition is critical for the ability of the pathogenic yeast Cryptococcus neoformans to cause disease in vertebrate hosts. In particular, iron overload exacerbates cryptococcal disease in an animal model, defects in iron acquisition attenuate virulence, and iron availability influences the expression of major virulence factors. C. neoformans acquires iron by multiple mechanisms, including a ferroxidase-permease high-affinity system, siderophore uptake, and utilization of both heme and transferrin. In this study, we examined the expression of eight candidate ferric reductase genes and their contributions to iron acquisition as well as to ferric and cupric reductase activities. We found that loss of the FRE4 gene resulted in a defect in production of the virulence factor melanin and increased susceptibility to azole antifungal drugs. In addition, the FRE2 gene was important for growth on the iron sources heme and transferrin, which are relevant for proliferation in the host. Fre2 may participate with the ferroxidase Cfo1 of the high-affinity uptake system for growth on heme, because a mutant lacking both genes showed a more pronounced growth defect than the fre2 single mutant. A role for Fre2 in iron acquisition is consistent with the attenuation of virulence observed for the fre2 mutant. This mutant also was defective in accumulation in the brains of infected mice, a phenotype previously observed for mutants with defects in high-affinity iron uptake (e.g., the cfo1 mutant). Overall, this study provides a more detailed view of the iron acquisition components required for C. neoformans to cause cryptococcosis.
获取铁元素对于致病性酵母新型隐球菌在脊椎动物宿主中引发疾病的能力至关重要。特别是，铁过载会加剧动物模型中的隐球菌病，铁获取缺陷会减弱毒力，而铁的可利用性会影响主要毒力因子的表达。新型隐球菌通过多种机制获取铁元素，包括铁氧化酶-通透酶高亲和力系统、铁载体摄取以及血红素和转铁蛋白的利用。在本研究中，我们检测了八个候选铁还原酶基因的表达及其对铁获取以及铁还原酶和铜还原酶活性的贡献。我们发现，FRE4基因的缺失导致毒力因子黑色素产生缺陷，并增加了对唑类抗真菌药物的敏感性。此外，FRE2基因对于在血红素和转铁蛋白等铁源上生长很重要，而这些铁源与在宿主体内增殖相关。Fre2可能与高亲和力摄取系统的铁氧化酶Cfo1共同参与在血红素上的生长，因为同时缺失这两个基因的突变体比fre2单突变体表现出更明显的生长缺陷。Fre2在铁获取中的作用与fre2突变体观察到的毒力减弱一致。该突变体在感染小鼠大脑中的积累也存在缺陷，这是先前在高亲和力铁摄取缺陷的突变体（如cfo1突变体）中观察到的一种表型。总体而言，本研究提供了关于新型隐球菌引发隐球菌病所需铁获取成分的更详细观点。
