Attenuated Plasmodium yoelii lacking purine nucleoside phosphorylase confer protective immunity.
Attenuated Plasmodium yoelii lacking purine nucleoside phosphorylase confer protective immunity.
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由于对已确定的抗疟药物出现抗药性以及缺乏有效的疫苗，疟疾继续在撒哈拉以南非洲肆虐。疟原虫物种具有独特的流线型嘌呤途径，其中双特异性酶嘌呤核苷磷酸化酶（PNP）在嘌呤再循环和嘌呤补救中起作用。为了评估PNP在疟疾体内模型中的重要性，我们破坏了PyPNP，即致死性约氏疟原虫YM株中编码PNP的基因。缺乏PNP的约氏疟原虫寄生虫在小鼠中减毒并清除。虽然能够形成配子母细胞，PNP缺陷型寄生虫没有形成卵囊在蚊子中肠，并没有从蚊子传播到小鼠。给予PNP缺陷型寄生虫的小鼠对随后的约氏疟原虫YM致死接种物的攻击和约氏疟原虫17 XNL（另一种菌株）的攻击具有免疫力。这些对缺乏PNP的寄生虫的体内研究支持将嘌呤补救作为抗疟药的靶点。他们还提出了一种策略，用于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。
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.