The Potential of Human Defensin 5 (HD5) as a Novel Strategy for Malaria Control: Inhibition of Plasmodium Development in Anopheles

Malaria is a serious threat to human health. The existing vector-based interventions have shortcomings, such as the environmental pollution and strong resistance to chemical insecticides, the relatively slow effects of biological insecticides. It is urgent to look for novel strategies to control malaria such as by reducing mosquito vector competence. Human defensin 5 (HD5) has broad-spectrum and high antimicrobial activity. We are intrigued whether HD5 can block malaria transmission by inhibition of plasmodium development in mosquitoes. So, HD5 was injected intrathoracically into Anopheles stephensi at various time points, and it was found that the infection intensity of Plasmodium yoelii in An. stephensi was significantly reduced by HD5 treatment at 24 h prior to infection or 6 h, 12 h, 24 h post-infection, comparing with the control groups. Then, we found that HD5 treatment significantly up-regulated TEP1 expression at 24 h and 72 h post-infection (hpi), while the expression of MyD88 and Rel1 in the Toll pathway were up-regulated at 24 hpi. Furthermore, RNA interference of MyD88 which is the key upstream molecule of Toll signaling pathway abolished the HD5-induced resistance of mosquitoes against malaria parasites infection. These results indicated HD5 microinjection to mosquito could effectively inhibit the development of malaria parasites in An. stephensi via activating the Toll signaling pathway. This study provides theoretical reference for the application of HD5 in malaria transmission blocking strategies using genetic engineering or transfection methods.