Fitness of sulfadoxine-resistant Plasmodium berghei harboring a single mutation in dihydropteroate synthase (dhps).
Fitness of sulfadoxine-resistant Plasmodium berghei harboring a single mutation in dihydropteroate synthase (dhps).
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具有二氢蝶酸合酶 (dhps) 单一突变的磺胺多辛抗性伯氏疟原虫的适应性。
DOI：
10.1016/j.actatropica.2021.106049
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发表时间：
2021
期刊：
影响因子：
--
通讯作者：
Mita T.
中科院分区：
文献类型：
--
作者：
Yamauchi M;Hirai M;Tachibana SI;Mori T;Mita T.
通常认为，在没有药物的情况下，赋予耐药性的基因变化会给病原体带来适应性成本。然而，恶性疟原虫对磺胺多辛/乙胺嘧啶耐药的适应性尚无定论。这是因为耐药性是由二氢叶酸合酶（dhps）和二氢叶酸还原酶（dhfr）突变的复杂组合赋予的，这使得很难单独评估dhps和dhfr突变造成的成本的程度和幅度。为了评估单抗磺胺多辛带来的适应度成本，我们培育了一种携带dhps A394G突变（PbDHPS-A394G）的转基因啮齿动物疟原虫，该突变与恶性疟原虫磺胺多辛抗性的致病突变（PfDHPS-A437G）相对应。为期四天的抑制试验证实PbDHPS-A394G克隆对磺胺多辛具有抗性。PbDHPS-A394G与野生型克隆表现出相似的生长速率和配子体产量。将PbDHPS-A394G与野生型克隆共感染小鼠，直接评估它们之间的生存竞争，在竞争实验中证实了这一观察结果。在蚊子中，PbDHPS-A394G与野生型的卵囊产量无显著差异。这些结果表明，PbDHPS-A394G突变改变了寄生虫对磺胺多啶的抗性，但在小鼠血液期和蚊子卵囊形成期间可能不会造成适应度不利。这些结果部分解释了PfDHPS-A437G突变体在天然寄生虫种群中的持久性。
Genetic changes conferring drug resistance are generally believed to impose fitness costs to pathogens in the absence of the drug. However, the fitness of resistant parasites against sulfadoxine/pyrimethamine has been inconclusive in Plasmodium falciparum. This is because resistance is conferred by the complex combination of mutations in dihydropteroate synthase (dhps) and dihydrofolate reductase (dhfr), which makes it difficult to separately assess the extent and magnitude of the costs imposed by mutations in dhps and dhfr. To assess the fitness costs imposed by sulfadoxine resistance alone, we generated a transgenic rodent malaria parasite, P. berghei clone harboring an A394G mutation in dhps (PbDHPS-A394G), corresponding to the causative mutation for sulfadoxine resistance in P. falciparum (PfDHPS-A437G). A four-day suppressive test confirmed that the PbDHPS-A394G clone was resistant to sulfadoxine. PbDHPS-A394G and wild-type clones showed similar growth rates and gametocyte production. This observation was confirmed in competitive experiments in which PbDHPS-A394G and wild-type clones were co-infected into mice to directly assess the survival competition between them. In the mosquitoes, there were no significant differences in oocyst production between PbDHPS-A394G and wildtype. These results indicate that the PbDHPS-A394G mutation alters the parasites to sulfadoxine resistance but may not impose fitness disadvantages during the blood stages in mice and oocyst formation in mosquitoes. These results partly explain the persistence of the PfDHPS-A437G mutant in the natural parasite populations.