CHLOROQUINE INDUCES HUMAN MACROPHAGE KILLING OF HISTOPLASMA-CAPSULATUM BY LIMITING THE AVAILABILITY OF INTRACELLULAR IRON AND IS THERAPEUTIC IN A MURINE MODEL OF HISTOPLASMOSIS
CHLOROQUINE INDUCES HUMAN MACROPHAGE KILLING OF HISTOPLASMA-CAPSULATUM BY LIMITING THE AVAILABILITY OF INTRACELLULAR IRON AND IS THERAPEUTIC IN A MURINE MODEL OF HISTOPLASMOSIS
复制标题
DOI：
10.1172/jci117119
复制
发表时间：
1994-04-01
影响因子：
15.9
通讯作者：
DEEPE, GS
中科院分区：
文献类型：
--
作者：
NEWMAN, SL;GOOTEE, L;DEEPE, GS
我们研究了细胞内铁对荚膜组织胞浆菌（HC）酵母在人巨噬细胞（M phi）内增殖能力的作用。与铁螯合剂去铁胺共培养的HC感染的M phi抑制酵母的生长在浓度依赖性的方式。去铁胺的作用被铁饱和转铁蛋白（全转铁蛋白）逆转，但不被无铁转铁蛋白（脱铁转铁蛋白）逆转。氯喹通过提高内吞和溶酶体pH值来阻止铁从转铁蛋白中释放，诱导人M phi杀死Hc。氯喹（40-120 mg/kg）腹腔注射6 d可明显抑制HC的生长，并呈剂量依赖性。在120 mg/kg剂量下，脾脏和肝脏中的CFU分别减少了17倍和15倍（P < 0.01）。氯喹的治疗效果也与治疗时间长短有关。当在感染后第5天开始氯喹治疗（120 mg/kg）时，仅2天，脾脏中的CFU就减少了50%。在接种致死的Hc后用氯喹治疗10天，9只小鼠中有6只得到保护;所有对照小鼠在第11天死亡（B）体外实验表明，氯喹通过限制胞内铁的利用率，诱导Hc酵母细胞的死亡;和（c）在体内，氯喹显著减少HC感染小鼠脾和肝中的生物体数量，并可保护小鼠免受HC酵母的致死接种物的侵害。因此，氯喹可有效治疗活动性组织胞浆菌病，也可用于预防获得性免疫缺陷综合征患者组织胞浆菌病复发。
We investigated the role of intracellular iron on the capacity of Histoplasma capsulatum (Hc) yeasts to multiply within human macrophages (M phi). Coculture of Hc-infected M phi with the iron chelator deferoxamine suppressed the growth of yeasts in a concentration-dependent manner. The effect of deferoxamine was reversed by iron-saturated transferrin (holotransferrin) but not by iron-free transferrin (apotransferrin). Chloroquine, which prevents release of iron from transferrin by raising endocytic and lysosomal pH, induced human M phi to kill Hc. The effect of chloroquine was reversed by iron nitriloacetate, an iron compound that is soluble at neutral to alkaline pH, but not by holotransferrin, which releases iron only in an acidic environment.Chloroquine (40-120 mg/kg) given intraperitoneally for 6 d to Hc-infected C57BL/6 mice significantly reduced the growth of Hc in a dose-dependent manner. At 120 mg/kg there was a 17- and 15-fold reduction (P < 0.01) in CFU in spleens and livers, respectively. The therapeutic effect of chloroquine also correlated with the length of treatment. As little as 2 d of chloroquine therapy (120 mg/kg), when started at day 5 after infection, reduced CFU in tbe spleen by 50%. Treatment with chloroquine for 10 d after a lethal inoculum of Hc protected six of nine mice; all control mice were dead by day 11 (P = 0.009).This study demonstrates that: (a) iron is of critical importance to the survival and multiplication of Hc yeasts in human M phi; (b) in vitro, chloroquine induces M phi killing of Hc yeasts by restricting the availability of intracellular iron; and (c) in vivo, chloroquine significantly reduces the number of organisms in the spleens and livers of Hc-infected mice and can protect mice from a lethal inoculum of Hc yeasts. Thus, chloroquine may be effective in the treatment of active histoplasmosis and also may be useful in preventing relapse of histoplasmosis in patients with acquired immunodeficiency syndromes.