Macrophage activation by IFN-γ triggers restriction of phagosomal copper from intracellular pathogens.
Macrophage activation by IFN-γ triggers restriction of phagosomal copper from intracellular pathogens.
复制标题
DOI：
10.1371/journal.ppat.1007444
复制
发表时间：
2018-11
期刊：
影响因子：
6.7
通讯作者：
Rappleye CA
中科院分区：
文献类型：
--
作者：
Shen Q;Beucler MJ;Ray SC;Rappleye CA
铜毒和铜限制都可以是有效的宿主防御机制。真菌对高铜的耐受性使得毒性作为防御机制对真菌病原体基本无效。对不能在巨噬细胞内复制的荚膜组织胞浆菌突变酵母的正向遗传筛选显示Ctr3铜转运蛋白是巨噬细胞内增殖所必需的。Ctr3介导铜的吸收，并且是在低铜下生长所必需的。CTR3基因的转录是由H.结果表明，低有效铜对病原酵母的致病性有一定的影响，而低有效铁对病原酵母的致病性无明显影响。细胞内酵母的CTR 3转录报告基因的低表达意味着非活化巨噬细胞的吞噬体具有中等的铜水平。这进一步得到了非活化巨噬细胞吞噬体内Ctr3缺陷型酵母复制的支持。然而，吞噬细胞的IFN-γ激活会导致吞噬体铜的限制，正如CTR3转录报告基因的上调以及Ctr3缺陷酵母（但不是Ctr3表达酵母）未能在这些巨噬细胞内增殖所示。因此，在组织胞浆菌病的呼吸道模型中，Ctr3缺陷型酵母在先天免疫应答阶段是完全毒性的，但在适应性免疫开始后减弱。因此，尽管技术限制阻止了吞噬体铜浓度的直接测量，并且铜非依赖性因素可以影响基因表达，但CTR 3启动子诱导和Ctr3缺陷型酵母的衰减都表明巨噬细胞的激活将吞噬体从铜充足的环境切换到铜耗尽的环境，迫使H. capsulatum依赖Ctr3获取铜。控制感染吞噬细胞的主要病原体通常需要获得性免疫，但将宿主细胞从允许状态转换为抗菌状态的机制仅部分了解。胞内真菌病原体荚膜组织胞浆菌在巨噬细胞吞噬体内驻留和增殖。在先天免疫中，通常控制真菌的巨噬细胞对H.荚膜酵母在此阶段，未活化的巨噬细胞的吞噬体具有充足的铜，其促进组织胞浆菌的细胞内生长，但不引起铜毒性。然而，适应性免疫的发生和随后的巨噬细胞活化降低了吞噬体铜，巨噬细胞变得不太允许组织胞浆菌增殖。IFN-γ作为一种关键的细胞因子，通过将吞噬体从铜充足状态改变为铜耗尽状态来切换巨噬细胞策略，以控制细胞内病原体。在这种活化的巨噬细胞中，H. capsulatum酵母上调Ctr3铜转运蛋白的表达，以使必需铜的持续获取成为可能。
Copper toxicity and copper limitation can both be effective host defense mechanisms against pathogens. Tolerance of high copper by fungi makes toxicity as a defense mechanism largely ineffective against fungal pathogens. A forward genetic screen for Histoplasma capsulatum mutant yeasts unable to replicate within macrophages showed the Ctr3 copper transporter is required for intramacrophage proliferation. Ctr3 mediates copper uptake and is required for growth in low copper. Transcription of the CTR3 gene is induced by differentiation of H. capsulatum into pathogenic yeasts and by low available copper, but not decreased iron. Low expression of a CTR3 transcriptional reporter by intracellular yeasts implies that phagosomes of non-activated macrophages have moderate copper levels. This is further supported by the replication of Ctr3-deficient yeasts within the phagosome of non-activated macrophages. However, IFN-γ activation of phagocytes causes restriction of phagosomal copper as shown by upregulation of the CTR3 transcriptional reporter and by the failure of Ctr3-deficient yeasts, but not Ctr3 expressing yeasts, to proliferate within these macrophages. Accordingly, in a respiratory model of histoplasmosis, Ctr3-deficient yeasts are fully virulent during phases of the innate immune response but are attenuated after the onset of adaptive immunity. Thus, while technical limitations prevent direct measurement of phagosomal copper concentrations and copper-independent factors can influence gene expression, both the CTR3 promoter induction and the attenuation of Ctr3-deficient yeasts indicate activation of macrophages switches the phagosome from a copper-replete to a copper-depleted environment, forcing H. capsulatum reliance on Ctr3 for copper acquisition. Control of primary pathogens that infect phagocytes often requires adaptive immunity, but the mechanisms that convert host cells from permissive to antimicrobial states are only partially understood. The intracellular fungal pathogen Histoplasma capsulatum resides and proliferates within the macrophage phagosome. During innate immunity, macrophages which normally control fungi prove ineffective against H. capsulatum yeasts. At this stage, the phagosome of unactivated macrophages has ample copper that facilitates intracellular growth of Histoplasma but does not cause copper toxicity. However, the onset of adaptive immunity and the subsequent activation of macrophages decreases phagosomal copper and macrophages become less permissive to Histoplasma proliferation. IFN-γ acts as a key cytokine for switching the macrophage strategy by changing phagosomes from a copper-sufficient to a copper-depleted state in order to control intracellular pathogens. In such activated macrophages, H. capsulatum yeasts upregulate expression of the Ctr3 copper transporter to enable continued acquisition of essential copper.
登录
查看更多内容
影响因子：
9.2
作者：
Alvarez, Mauricio;Casadevall, Arturo
通讯作者：
Casadevall, Arturo
结核分枝杆菌的外塞蛋白从人体结合蛋白中去除铁，并将铁捐赠给结核分枝杆菌细胞壁中的霉菌素。
影响因子：
15.3
作者：
Gobin, J;Horwitz, MA
通讯作者：
Horwitz, MA
影响因子：
6.7
作者：
Citiulo F;Jacobsen ID;Miramón P;Schild L;Brunke S;Zipfel P;Brock M;Hube B;Wilson D
通讯作者：
Wilson D
影响因子：
3.6
作者：
Ding C;Yin J;Tovar EM;Fitzpatrick DA;Higgins DG;Thiele DJ
通讯作者：
Thiele DJ
影响因子：
4.9
作者：
Edwards, Jessica A.;Kemski, Megan M.;Rappleye, Chad A.
通讯作者：
Rappleye, Chad A.