The Department of Biochemistry and Molecular Biology, Johns Hopkins University Bloomberg School of Public Health, Baltimore, MD 21205, USA.
Department of Biochemistry, University of Missouri, Columbia, MO 65211, USA.
Metallomics. 2020 Mar 25;12(3):416-426. doi: 10.1039/c9mt00294d.
Animals carefully control homeostasis of Cu, a metal that is both potentially toxic and an essential nutrient. During infection, various shifts in Cu homeostasis can ensue. In mice infected with Candida albicans, serum Cu progressively rises and at late stages of infection, liver Cu rises, while kidney Cu declines. The basis for these changes in Cu homeostasis was poorly understood. We report here that the progressive rise in serum Cu is attributable to liver production of the multicopper oxidase ceruloplasmin (Cp). Through studies using Cp-/- mice, we find this elevated Cp helps recover serum Fe levels at late stages of infection, consistent with a role for Cp in loading transferrin with Fe. Cp also accounts for the elevation in liver Cu seen during infection, but not for the fluctuations in kidney Cu. The Cu exporting ATPase ATP7B is one candidate for kidney Cu control, but we find no change in the pattern of kidney Cu loss during infection of Atp7b-/- mice, implying alternative mechanisms. To test whether fungal infiltration of kidney tissue was required for kidney Cu loss, we explored other paradigms of infection. Infection with the intravascular malaria parasite Plasmodium berghei caused a rise in serum Cu and decrease in kidney Cu similar to that seen with C. albicans. Thus, dynamics in kidney Cu homeostasis appear to be a common feature among vastly different infection paradigms. The implications for such Cu homeostasis control in immunity are discussed.
动物会精细地控制铜（Cu）的体内平衡，Cu 既是一种潜在的毒性物质，也是一种必需的营养物质。在感染期间，Cu 的体内平衡可能会发生各种变化。在感染白色念珠菌（Candida albicans）的小鼠中，血清 Cu 逐渐升高，在感染后期，肝脏 Cu 升高，而肾脏 Cu 下降。这些 Cu 体内平衡变化的基础知之甚少。我们在此报告，血清 Cu 的逐渐升高归因于肝脏产生的多铜氧化酶铜蓝蛋白（Cp）。通过使用 Cp-/- 小鼠进行的研究，我们发现这种升高的 Cp 有助于在感染后期恢复血清 Fe 水平，表明 Cp 在将 Fe 加载到转铁蛋白中起作用。Cp 还解释了感染期间肝脏 Cu 的升高，但不能解释肾脏 Cu 的波动。Cu 输出 ATP 酶 ATP7B 是控制肾脏 Cu 的一个候选者，但我们发现感染 Atp7b-/- 小鼠时肾脏 Cu 丢失的模式没有变化，这意味着存在替代机制。为了测试肾脏组织中真菌浸润是否是肾脏 Cu 丢失所必需的，我们探索了其他感染范例。感染血腔疟原虫（Plasmodium berghei）导致血清 Cu 升高和肾脏 Cu 降低，与白色念珠菌感染相似。因此，肾脏 Cu 体内平衡的动态似乎是截然不同的感染范例的共同特征。讨论了这种 Cu 体内平衡控制对免疫的影响。
