美國斯坦福大學(xué)醫(yī)學(xué)院和加利福尼亞大學(xué)舊金山分?？茖W(xué)家通過一種新奇的“馴化”技術(shù),，讓瘧原蟲必須依賴一種外來化學(xué)物質(zhì)的供給才能活命，造出了一種“馴化瘧原蟲”,。這種馴化瘧原蟲毒性大大減弱,，并可能激發(fā)人體免疫系統(tǒng)反應(yīng)，從而為開發(fā)首個抗瘧疾疫苗提供了依據(jù),。該研究發(fā)表在8月30日的《公共科學(xué)圖書館—生物學(xué)》上,。
瘧原蟲是一種單細胞變形蟲，能導(dǎo)致瘧疾。它們在蚊子體內(nèi),、人體肝臟和血液中表現(xiàn)為不同的外形,，以躲過免疫系統(tǒng)攻擊。它們在人體肝臟內(nèi)不顯出癥狀,，進入紅細胞后會大量繁殖,，使紅細胞破碎，造成了病人冷熱交替的癥狀,。
研究人員發(fā)現(xiàn),，瘧原蟲進入血細胞后,，要想存活必須依賴一種基本物質(zhì)異戊烯焦磷酸（IPP）,。正常情況下，IPP由一種獨特的細胞器apicoplast合成供給,，而這種細胞器是瘧原蟲獨有的,。
他們給血液階段的瘧原蟲飼喂了一種抗生素，這種抗生素能讓瘧原蟲與apicoplast分離,，使它們最終死亡,，但只用這種抗生素療效很慢。如果把抗生素和IPP共同加入培養(yǎng)基,，瘧原蟲仍會大量繁殖,。
“這表明在apicoplast合成的多種物質(zhì)中，IPP是瘧原蟲在血液階段唯一真正需要的,。”斯坦福大學(xué)病理學(xué)系的艾倫·雅解釋說,，由于哺乳動物制造IPP的途徑和瘧原蟲完全不同，所以能破壞瘧原蟲合成IPP功能的藥物,，并不會損害人類細胞合成IPP的能力,，也能清除瘧原蟲。
瘧原蟲每年造成大約100萬人死亡,，世界上每年新發(fā)的瘧疾病例超過2.5億,，目前尚無有效的瘧疾疫苗。盡管青蒿素仍然有效,，但據(jù)報道已發(fā)現(xiàn)了有抗藥性的瘧原蟲,。艾倫·雅說：“如果抗藥性瘧原蟲流行開來，我們會陷入大麻煩,，因為幾乎所有的療法都是基于青蒿素,。而apicoplast是重要的藥物靶點，瞄準(zhǔn)其功能是開發(fā)抵抗瘧疾療法的新方向,。”(生物谷 Bioon.com)
doi:10.1371/journal.pbio.1001138
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PMID:
Chemical Rescue of Malaria Parasites Lacking an Apicoplast Defines Organelle Function in Blood-Stage Plasmodium falciparum
Ellen Yeh, Joseph L. DeRisi
Plasmodium spp parasites harbor an unusual plastid organelle called the apicoplast. Due to its prokaryotic origin and essential function, the apicoplast is a key target for development of new anti-malarials. Over 500 proteins are predicted to localize to this organelle and several prokaryotic biochemical pathways have been annotated, yet the essential role of the apicoplast during human infection remains a mystery. Previous work showed that treatment with fosmidomycin, an inhibitor of non-mevalonate isoprenoid precursor biosynthesis in the apicoplast, inhibits the growth of blood-stage P. falciparum. Herein, we demonstrate that fosmidomycin inhibition can be chemically rescued by supplementation with isopentenyl pyrophosphate (IPP), the pathway product. Surprisingly, IPP supplementation also completely reverses death following treatment with antibiotics that cause loss of the apicoplast. We show that antibiotic-treated parasites rescued with IPP over multiple cycles specifically lose their apicoplast genome and fail to process or localize organelle proteins, rendering them functionally apicoplast-minus. Despite the loss of this essential organelle, these apicoplast-minus auxotrophs can be grown indefinitely in asexual blood stage culture but are entirely dependent on exogenous IPP for survival. These findings indicate that isoprenoid precursor biosynthesis is the only essential function of the apicoplast during blood-stage growth. Moreover, apicoplast-minus P. falciparum strains will be a powerful tool for further investigation of apicoplast biology as well as drug and vaccine development.
