Ferrer Patricia, Vega-Rodriguez Joel, Tripathi Abhai K, Jacobs-Lorena Marcelo, Sullivan David J
The W. Harry Feinstone Department of Molecular Microbiology and Immunology, Malaria Research Institute, Bloomberg School of Public Health, Johns Hopkins University, Baltimore, Maryland, USA.
The W. Harry Feinstone Department of Molecular Microbiology and Immunology, Malaria Research Institute, Bloomberg School of Public Health, Johns Hopkins University, Baltimore, Maryland, USA
Antimicrob Agents Chemother. 2015 Mar;59(3):1418-26. doi: 10.1128/AAC.04642-14. Epub 2014 Dec 15.
Reducing the transmission of the malarial parasite by Anopheles mosquitoes using drugs or vaccines remains a main focus in the efforts to control malaria. Iron chelators have been studied as potential antimalarial drugs due to their activities against different stages of the parasite. The iron chelator FBS0701 affects the development of Plasmodium falciparum early gametocytes and lowers blood-stage parasitemia. Here, we tested the effect of FBS0701 on stage V gametocyte infectivity for mosquitoes. The incubation of stage V gametocytes for up to 3 days with increasing concentrations of FBS0701 resulted in a significant dose-related reduction in mosquito infectivity, as measured by the numbers of oocysts per mosquito. The reduction in mosquito infectivity was due to the inhibition of male and female gametocyte activation. The preincubation of FBS0701 with ferric chloride restored gametocyte infectivity, showing that the inhibitory effect of FBS0701 was quenched by iron. Deferoxamine, another iron chelator, also reduced gametocyte infectivity but to a lesser extent. Finally, the simultaneous administration of drug and gametocytes to mosquitoes without previous incubation did not significantly reduce the numbers of oocysts. These results show the importance of gametocyte iron metabolism as a potential target for new transmission-blocking strategies.
使用药物或疫苗减少按蚊传播疟原虫仍是疟疾防治工作的主要重点。由于铁螯合剂对疟原虫不同阶段具有活性，因此已被作为潜在的抗疟药物进行研究。铁螯合剂FBS0701会影响恶性疟原虫早期配子体的发育，并降低血期寄生虫血症。在此，我们测试了FBS0701对V期配子体感染蚊子能力的影响。用浓度不断增加的FBS0701孵育V期配子体长达3天，结果显示，以每只蚊子的卵囊数量衡量，蚊子的感染性出现了显著的剂量相关降低。蚊子感染性的降低是由于雌雄配子体激活受到抑制。FBS0701与氯化铁预孵育可恢复配子体的感染性，表明FBS0701的抑制作用可被铁淬灭。另一种铁螯合剂去铁胺也降低了配子体的感染性，但程度较小。最后，在未预先孵育的情况下将药物和配子体同时给予蚊子，并未显著减少卵囊数量。这些结果表明配子体铁代谢作为新的传播阻断策略潜在靶点的重要性。
