Parasitology Unit, Max Planck Institute for Infection Biology, 10117 Berlin.
Antimicrob Agents Chemother. 2011 Jun;55(6):2760-7. doi: 10.1128/AAC.01717-10. Epub 2011 Mar 28.
Each year, infections with the protozoan parasite Plasmodium falciparum kill 1 million people, mostly children in Africa. Intermittent preventive treatment (IPT) with sulfadoxine-pyrimethamine (SP) reduces the incidence of malaria and aims to prevent mortality in infants, children, and pregnant women. There is contradictory evidence as to whether this strategy may generate additional protection against reinfection beyond the limited duration of the intervention. Previous work established that ablation of either liver-stage maturation or subsequent life cycle conversion by causal prophylactic drugs elicits protective immune responses against reinfections when drugs are no longer present. Here we show in the rodent malaria model that pyrimethamine, a component of SP, inhibits liver-stage development in vitro and in vivo, confirming the causal prophylactic activity of pyrimethamine. Repeated exposure to high doses of Plasmodium berghei sporozoites during pyrimethamine prophylaxis induced complete protection in C57BL/6 mice against challenge with high doses of sporozoites delivered intravenously 35 to 199 days later. Immunizations by infectious mosquito bites induced limited, inoculation-dependent protection against subsequent challenge by infected mosquito bites but provided partial protection against experimental cerebral malaria. Short-term pyrimethamine prophylaxis during intravenous transmission of sporozoites from a pyrimethamine-resistant strain delayed, but did not prevent, blood-stage infection. Our data provide a rationale for the notion of sustained protective efficacy of IPT based on the capacity of arrested, drug-sensitive liver-stage and/or suppressed blood-stage parasites to mount lasting protection.
每年，疟原虫寄生虫恶性疟原虫感染导致 100 万人死亡，其中大多数是非洲的儿童。间歇性预防治疗（IPT）用磺胺多辛-乙胺嘧啶（SP）减少疟疾的发病率，并旨在预防婴儿、儿童和孕妇的死亡。关于这种策略是否可能在干预的有限持续时间之外产生对再感染的额外保护，存在矛盾的证据。以前的工作已经确定，通过因果预防性药物消除肝期成熟或随后的生活周期转化，在药物不再存在的情况下，会引发针对再感染的保护性免疫反应。在这里，我们在啮齿动物疟疾模型中表明，乙胺嘧啶是 SP 的一种成分，在体外和体内抑制肝期发育，证实了乙胺嘧啶的因果预防性活性。在乙胺嘧啶预防期间反复暴露于高剂量的疟原虫孢子虫可诱导 C57BL/6 小鼠对 35 至 199 天后静脉内给予高剂量孢子虫的挑战完全保护。通过感染性蚊子叮咬进行免疫接种可诱导对随后由感染性蚊子叮咬引起的挑战的有限、接种依赖性保护，但对实验性脑疟疾提供部分保护。在来自乙胺嘧啶耐药株的孢子虫经静脉传播期间进行短期乙胺嘧啶预防可延迟，但不能预防血期感染。我们的数据为基于被阻断的、药物敏感的肝期和/或被抑制的血期寄生虫的持久保护能力的 IPT 的持续保护效力的概念提供了依据。
