Candida albicans adapts to host copper during infection by swapping metal cofactors for superoxide dismutase
Candida albicans adapts to host copper during infection by swapping metal cofactors for superoxide dismutase
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DOI：
10.1073/pnas.1513447112
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发表时间：
2015-09-22
影响因子：
11.1
通讯作者：
Culotta, Valeria Cizewski
中科院分区：
文献类型：
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作者：
Li, Cissy X.;Gleason, Julie E.;Culotta, Valeria Cizewski
铜既是一种必需的营养物质，也是一种潜在的有毒金属，在感染过程中，宿主可以利用铜来控制病原体的生长。在这里，我们描述了一个聪明的适应铜所采取的人类真菌病原体白色念珠菌。在实验室培养的富铜条件下，C.白念珠菌表达的铜需要形式的超氧化物歧化酶（SOD 1）在胞质溶胶中，但当铜水平下降，细胞切换到一个替代锰需要SOD 3。Cu和Mn-SOD之间的这种切换由Cu感测调节器Mac 1控制，并确保C.白念珠菌保持恒定的SOD活性的胞质抗氧化保护，尽管波动铜。这种对Cu的反应是在C.白色念珠菌入侵的主机，其中酵母是暴露于广泛的变化，在铜。在播散性念珠菌病的小鼠模型中，发现血清Cu在感染过程中逐渐升高，但这种升高的Cu反应并没有反映在宿主组织中。作为真菌感染的主要部位的肾脏显示出铜的初始上升，随后金属的下降。C.白念珠菌相应地调整其胞质SODs，并在感染的早期表达Cu-Sod 1，随后诱导Mn-Sod 3，并增加CTR 1的表达以吸收Cu。总之，这些研究表明，真菌感染触发宿主Cu和C的显着波动。白色念珠菌通过调节铜的吸收和将金属辅因子交换为抗氧化剂SOD来轻易适应。
Copper is both an essential nutrient and potentially toxic metal, and during infection the host can exploit Cu in the control of pathogen growth. Here we describe a clever adaptation to Cu taken by the human fungal pathogen Candida albicans. In laboratory cultures with abundant Cu, C. albicans expresses a Cu-requiring form of superoxide dismutase (Sod1) in the cytosol; but when Cu levels decline, cells switch to an alternative Mn-requiring Sod3. This toggling between Cu- and Mn-SODs is controlled by the Cu-sensing regulator Mac1 and ensures that C. albicans maintains constant SOD activity for cytosolic antioxidant protection despite fluctuating Cu. This response to Cu is initiated during C. albicans invasion of the host where the yeast is exposed to wide variations in Cu. In a murine model of disseminated candidiasis, serum Cu was seen to progressively rise over the course of infection, but this heightened Cu response was not mirrored in host tissue. The kidney that serves as the major site of fungal infection showed an initial rise in Cu, followed by a decline in the metal. C. albicans adjusted its cytosolic SODs accordingly and expressed Cu-Sod1 at early stages of infection, followed by induction of Mn-Sod3 and increases in expression of CTR1 for Cu uptake. Together, these studies demonstrate that fungal infection triggers marked fluctuations in host Cu and C. albicans readily adapts by modulating Cu uptake and by exchanging metal cofactors for antioxidant SODs.