Targeting mosquito FREP1 with a fungal metabolite blocks malaria transmission.
Targeting mosquito FREP1 with a fungal metabolite blocks malaria transmission.
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DOI：
10.1038/srep14694
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发表时间：
2015-10-06
影响因子：
4.6
通讯作者：
Li J
中科院分区：
文献类型：
--
作者：
Niu G;Wang B;Zhang G;King JB;Cichewicz RH;Li J
抑制蚊子体内疟原虫的发育将阻止疟疾的传播。纤维蛋白原相关蛋白1（FREP 1）是冈比亚按蚊寄生虫感染的关键蛋白，通过与配子体和动合子相互作用促进疟原虫在蚊子体内的入侵。为了验证破坏这种相互作用的小分子将阻止寄生虫感染蚊子的假设，我们开发了一种基于ELISA的方法来筛选真菌提取物文库。我们获得了尼日尔曲霉的候选真菌提取物，其抑制FREP 1和恶性疟原虫感染细胞之间的相互作用约92%。通过免疫荧光试验证实了抑制特异性。值得注意的是，用候选真菌提取物喂养蚊子显著抑制了中肠中的恶性疟原虫感染，而没有细胞毒性或抑制恶性疟原虫配子母细胞或动合子的发育。一种阻止FREP 1与配子母细胞或动合子结合的生物活性天然产物被分离并鉴定为P-乳清蛋白。重要的是，无毒或无毒的杀虫剂显著降低了恶性疟原虫在蚊子中的感染强度。因此，破坏FREP 1和寄生虫之间的相互作用有效地减少了蚊子中的疟原虫感染。因此，用小分子靶向FREP 1是阻断疟疾传播的有效新方法。
Inhibiting Plasmodium development in mosquitoes will block malaria transmission. Fibrinogen-related protein 1 (FREP1) is critical for parasite infection in Anopheles gambiae and facilitates Plasmodium invasion in mosquitoes through interacting with gametocytes and ookinetes. To test the hypothesis that small molecules that disrupt this interaction will prevent parasites from infecting mosquitoes, we developed an ELISA-based method to screen a fungal extract library. We obtained a candidate fungal extract of Aspergillus niger that inhibited the interaction between FREP1 and P. falciparum infected cells by about 92%. The inhibition specificity was confirmed by immunofluorescence assays. Notably, feeding mosquitoes with the candidate fungal extract significantly inhibited P. falciparum infection in the midgut without cytotoxicity or inhibition of the development of P. falciparum gametocytes or ookinetes. A bioactive natural product that prevents FREP1 from binding to gametocytes or ookinetes was isolated and identified as P-orlandin. Importantly, the nontoxic orlandin significantly reduced P. falciparum infection intensity in mosquitoes. Therefore, disruption of the interaction between FREP1 and parasites effectively reduces Plasmodium infection in mosquitoes. Targeting FREP1 with small molecules is thus an effective novel approach to block malaria transmission.