Ting Li-Min, Gissot Mathieu, Coppi Alida, Sinnis Photini, Kim Kami
Department of Medicine and Microbiology, Albert Einstein College of Medicine, 1300 Morris Park Avenue, Bronx, New York 10461, USA.
Nat Med. 2008 Sep;14(9):954-8. doi: 10.1038/nm.1867.
Malaria continues to devastate sub-Saharan Africa owing to the emergence of drug resistance to established antimalarials and to the lack of an efficacious vaccine. Plasmodium species have a unique streamlined purine pathway in which the dual specificity enzyme purine nucleoside phosphorylase (PNP) functions in both purine recycling and purine salvage. To evaluate the importance of PNP in an in vivo model of malaria, we disrupted PyPNP, the gene encoding PNP in the lethal Plasmodium yoelii YM strain. P. yoelii parasites lacking PNP were attenuated and cleared in mice. Although able to form gametocytes, PNP-deficient parasites did not form oocysts in mosquito midguts and were not transmitted from mosquitoes to mice. Mice given PNP-deficient parasites were immune to subsequent challenge to a lethal inoculum of P. yoelii YM and to challenge from P. yoelii 17XNL, another strain. These in vivo studies with PNP-deficient parasites support purine salvage as a target for antimalarials. They also suggest a strategy for the development of attenuated nontransmissible metabolic mutants as blood-stage malaria vaccine strains.
由于对现有抗疟药物产生耐药性以及缺乏有效的疫苗，疟疾继续在撒哈拉以南非洲地区肆虐。疟原虫具有独特的简化嘌呤途径，其中双特异性酶嘌呤核苷磷酸化酶（PNP）在嘌呤循环和嘌呤补救中均发挥作用。为了评估PNP在疟疾体内模型中的重要性，我们破坏了致死性约氏疟原虫YM株中编码PNP的基因PyPNP。缺乏PNP的约氏疟原虫在小鼠体内减毒并被清除。尽管能够形成配子体，但缺乏PNP的寄生虫在蚊中肠中未形成卵囊，也未从蚊子传播到小鼠。接受缺乏PNP的寄生虫的小鼠对随后的约氏疟原虫YM致死接种物攻击以及另一株约氏疟原虫17XNL的攻击具有免疫力。这些对缺乏PNP的寄生虫进行的体内研究支持将嘌呤补救作为抗疟药物的靶点。它们还提出了一种开发减毒的非传播性代谢突变体作为血液阶段疟疾疫苗株的策略。
