Hypothesis links emergence of chloroquine-resistant malaria and other intracellular pathogens and suggests a new strategy for treatment of diseases caused by intracellular parasites
Hypothesis links emergence of chloroquine-resistant malaria and other intracellular pathogens and suggests a new strategy for treatment of diseases caused by intracellular parasites
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DOI：
10.1016/j.mehy.2003.12.004
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发表时间：
2004-01-01
影响因子：
4.7
通讯作者：
Parris, GE
中科院分区：
文献类型：
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作者：
Parris, GE
氯喹和相关抗疟疾药物似乎通过抑制 NF-κ-B 来促进 T 细胞凋亡，NF-κ-B 会增强抗凋亡蛋白（例如 Bcl-2）的表达。因此，氯喹已在自身免疫性疾病中得到应用，它显然可以促进异常持续性 T 细胞的凋亡。克隆。氯喹预防疟疾的作用方式尚不清楚，但可能是通过促进受感染宿主细胞的过早凋亡来最大程度地减少寄生虫在肝细胞中的复制，这种复制发生在红细胞入侵之前。 20世纪50年代在世界范围内引入氯喹用于预防后，出现了对氯喹具有抗药性的疟疾。这里假设，在出现抗氯喹疟疾（可能具有增强的抗细胞凋亡能力）的同时，其他细胞内寄生虫已经进化以增强其防止宿主细胞细胞凋亡的能力。抗氯喹疟疾高发地区出现的病毒性疾病的两个例子是由艾滋病毒引起的艾滋病和由冠状病毒引起的SARS。该假说认为，预防性接触促凋亡氯喹药物会导致病毒株和其他具有增强抗凋亡能力的寄生虫的自然选择。当传播到不受促凋亡药物影响的宿主生物体时，新的“抗凋亡”菌株可能会引起意想不到的疾病。就 SARS 而言，冠状病毒似乎已经进入了一个新的生态位，并被证明对其宿主具有致命性。就艾滋病而言，HIV（与灵长类动物有长期共生关系）已经肆虐，因为受感染的细胞现在比未受感染的旁观者细胞对它们分泌的毒素（即对细胞凋亡具有抵抗力）更加耐受，而未感染的旁观者细胞通常对细胞凋亡具有抵抗力。该假设的一个推论是，如果受感染细胞对细胞凋亡的抵抗水平不高于旁观者细胞的抵抗水平，那么受感染细胞将优先通过细胞凋亡杀死自己。就 HIV 而言，Bcl-2 的表达和 p53 的抑制似乎增强了对细胞凋亡的抵抗力。因此，抑制 Bcl-2 或恢复 p53 功能的药物可能有效恢复感染细胞和未感染细胞之间对细胞凋亡的抵抗力。目前，一种针对 Bcl-2 的反义药物（G3139/Genasense™，Genta, Inc.）正处于晚期癌症试验中，可能在几个月内针对这些适应症上市。尝试这些药物对抗包括艾滋病毒在内的各种细胞内寄生虫将会很有趣。当没有安全有效的疫苗时，这种预防或消除活动性感染的方法可能对一系列寄生虫（病毒、细菌、原生动物、真菌）特别有吸引力。 (C) 2003 Elsevier Ltd. 保留所有权利。
Chloroquine and related anti-malarial drugs appear to promote apoptosis in T-cells by suppressing NF-kappa-B, which enhances the expression of anti-apoptotic proteins (e.g., Bcl-2). Thus, chloroquine has found applications in autoimmune diseases where it apparently facilitates apoptosis of abnormally persistent T-cell. clones. The mode of action of chloroquine in prevention of malaria is not known, but it may be to minimize replication of the parasite in the liver cells, which occurs before invasion of the erythrocytes, by facilitating premature apoptosis of the infected host cells. After introduction of chloroquine in the 1950s world-wide for prophylactic use, chloroquine-resistant malaria emerged. Here it is hypothesized that concurrent with emergence of chloroquine-resistant malaria (presumably with enhanced anti-apoptotic capabilities), other intracellular parasites have evolved to enhance their ability to prevent apoptosis in host cells. Two examples of viral diseases that have emerged from areas of high incidence of chloroquine-resistant malaria are AIDS from HIV and SARS from coronavirus. The hypothesis holds that prophylactic exposure to proapoptotic chloroquine drugs caused natural selection for strains of viruses and other parasites that have enhanced antiapoptotic abilities. When transmitted to host organisms that are not under the influence of the pro-apoptotic drug, the new "anti-apoptotic" strains may cause unexpected diseases. In the case of SARS, the coronavirus appears to have accessed a new niche where it proves to be Lethal to its host. In the case of AIDS, the HIV (which has had a long-term symbiotic relationship with primates) has run amuck because the infected cells are now substantially more tolerant to the toxins (i.e., resistant to apoptosis) that they secrete than the uninfected bystander cells, which are not unusually resistant to apoptosis. A corollary to the hypothesis is that if the level of resistance to apoptosis in the infected cells were no higher than the level of resistance in the bystander cells, then the infected cells would preferentially kill themselves through apoptosis. It appears that in the case of HIV, the increased resistance to apoptosis is provided by expression of Bcl-2 and suppression of p53. Hence, drugs that suppresses Bcl-2 or restore p53 function might be effective in restoring the parity of resistance to apoptosis between infected and uninfected cells. Currently, an antisense drug targeting Bcl-2 (G3139/Genasense(TM), Genta, Inc.) is in late-stage cancer trials and may be on the market for those indications in months. It would be interesting to try these drugs against various intracellular parasites including HIV. This approach to prevent or eliminate active infections might be particularly attractive against a range of parasites (virus, bacteria, protozoa, fungus) when safe and effective vaccines are not available. (C) 2003 Elsevier Ltd. All rights reserved.