Chloroquine induces human mononuclear phagocytes to inhibit and kill Cryptococcus neoformans by a mechanism independent of iron deprivation
Chloroquine induces human mononuclear phagocytes to inhibit and kill Cryptococcus neoformans by a mechanism independent of iron deprivation
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DOI：
10.1172/jci119688
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发表时间：
1997-09-15
影响因子：
15.9
通讯作者：
Liu, XP
中科院分区：
文献类型：
--
作者：
Levitz, SM;Harrison, TS;Liu, XP
由新生隐球菌引起的感染在艾滋病患者中很常见。我们研究了氯喹对单核巨噬细胞抗隐球菌活性的影响，氯喹可提高吞噬小体的pH，在没有氯喹的情况下，新生杆菌在单核巨噬细胞(MDM)内繁殖，但加入氯喹后，新生杆菌被杀死。氯化铵也是有益的，表明这种作用是通过使吞噬酶体碱化来实现的，氯喹通过限制铁的有效性来抑制其他细胞内病原体的生长，然而，氯喹诱导的MDM抗隐球菌活性的增强不受硝酸铁的影响，这表明氯喹的作用机制不依赖于铁剥夺。新生隐球菌在无细胞培养基中的生长与pH呈负相关，提示氯喹对MDM抗隐球菌活性的部分影响可以用较高pH条件下相对较差的生长来解释，氯喹增强了MDM对除一株未被吞噬的大胶囊菌株外的所有受试隐球菌的抗隐球菌活性，氯喹单独在HIV感染和未感染供者的单核细胞中也有阳性作用，最后，氯喹对繁殖的和严重联合免疫缺陷小鼠的实验性隐球菌病有治疗作用。因此，氯喹通过铁非依赖、pH依赖的机制增强单核巨噬细胞对新生隐球菌病的活性，并对隐球菌病的小鼠模型具有治疗作用，氯喹可能对预防和治疗人类隐球菌病具有临床应用价值。
Infections due to Cryptococcus neoformans are common in AIDS patients. We investigated the effect of chloroquine, which raises the pH of phagolysosomes, on the anticryptococcal activity of mononuclear phagocytes, C, neoformans multiplied within monocyte-derived macrophages (MDM) in the absence of chloroquine but were killed with the addition of chloroquine. Ammonium chloride was also beneficial, suggesting that effects were mediated by alkalinizing the phagolysosome, Chloroquine inhibits growth of other intracellular pathogens by limiting iron availability, However, chloroquine-induced augmentation of MDM anticryptococcal activity was unaffected by iron nitriloacetate, demonstrating that chloroquine worked by a mechanism independent of iron deprivation. There was an inverse correlation between growth of C. neoformans in cell-free media and pH, suggesting that some of the effect of chloroquine on the anticryptococcal activity of MDM could be explained by relatively poor growth at higher pH, Chloroquine enhanced MDM anticryptococcal activity against all tested cryptococcal strains except for one large-capsule strain which was not phagocytosed, Positive effects of chloroquine mere also seen in monocytes from both HIV-infected and -uninfected donors, Finally, chloroquine was therapeutic in experimental cryptococcosis in outbred and severe combined immunodeficient mice. Thus, chloroquine enhances the activity of mononuclear phagocytes against C. neoformans by iron-independent, pH-dependent mechanisms and is therapeutic in murine models of cryptococcosis, Chloroquine might have clinical utility for the prophylaxis and treatment of human cryptococcosis.