Copper is a trace metal that is necessary for all organisms but toxic when present in excess. Different mechanisms to avoid copper toxicity have been reported to date in pathogenic organisms such as Cryptococcus neoformans and Candida albicans. However, little if anything is known about pathogenic protozoans despite their importance in human and veterinary medicine. Naegleria fowleri is a free-living amoeba that occurs naturally in warm fresh water and can cause a rapid and deadly brain infection called primary amoebic meningoencephalitis (PAM). Here, we describe the mechanisms employed by N. fowleri to tolerate high copper concentrations, which include various strategies such as copper efflux mediated by a copper-translocating ATPase and upregulation of the expression of antioxidant enzymes and obscure hemerythrin-like and protoglobin-like proteins. The combination of different mechanisms efficiently protects the cell and ensures its high copper tolerance, which can be advantageous both in the natural environment and in the host. Nevertheless, we demonstrate that copper ionophores are potent antiamoebic agents; thus, copper metabolism may be considered a therapeutic target.

铜是一种微量金属，对所有生物都是必需的，但过量时会产生毒性。迄今为止，已经报道了在病原体生物（例如新型隐球菌和白色念珠菌）中避免铜中毒的不同机制。然而，尽管致病性原生动物在人类医学和兽医学中很重要，但对它们知之甚少。Naegleria fowleri是一种自由生活的变形虫，自然存在于温暖的淡水中，可引起称为原发性阿米巴脑膜脑炎 (PAM) 的快速致命的脑部感染。在这里，我们描述了N. fowleri采用的机制耐受高铜浓度，其中包括各种策略，例如由铜转运 ATP 酶介导的铜流出和抗氧化酶表达的上调以及模糊的类血红素和原珠蛋白样蛋白。不同机制的组合有效地保护了细胞并确保其高铜耐受性，这在自然环境和宿主中都是有利的。尽管如此，我们证明铜离子载体是有效的抗阿米巴药物。因此，铜代谢可能被认为是一个治疗目标。