Targeting mosquito FREP1 protein for malaria control

靶向蚊子 FREP1 蛋白控制疟疾

基本信息

批准号：
9446355
负责人：
Jun Li
金额：
$ 23.25万
依托单位：
FLORIDA INTERNATIONAL UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2015
资助国家：
美国
起止时间：
2015-05-01 至 2018-04-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9446355
关键词：
Targeting mosquito FREP1 protein malaria

项目摘要

DESCRIPTION (provided by applicant): Plasmodium infections are responsible for ~250 million clinical cases of malaria and nearly one million deaths each year worldwide. Plasmodium parasites are transmitted by anopheline mosquitoes, of which An. gambiae is the major vector in Africa. Although progress has been made towards the development of malaria vaccines, current strategies targeting liver and/or blood stage Plasmodium parasites will not stop disease transmission. Indeed, the long-term goal of malaria eradication will not be possible unless transmission is also blocked. To date, only one candidate transmission blocking vaccine (TBV) antigen (Pfs25) has reached clinical trial. However, Pfs25 cannot induce cross-species blocking (e.g. P. falciparum and P. vivax), and it cannot completely block malaria transmission. Thus, identification of additional TBV antigens that can prevent transmission of multiple clinically relevant species of Plasmodium and increase blocking efficacy remains a priority. The goals of this proposal are to evaluate a novel, highly conserved mosquito-expressed TBV vaccine candidate antigen and to use this molecule to identify additional TBV candidate antigens expressed by Plasmodium parasites. Recently, we reported that fibrinogen-related protein-1 (FREP1) expressed in An. gambiae is necessary for Plasmodium parasite infection in mosquitoes. New preliminary data show that FREP1 protein binds both rodent P. berghei and human P. falciparum infected red blood cells, suggesting that FREP1 is part of a highly conserved pathway of Plasmodium invasion in mosquitoes. Importantly, anti-FREP1 antibodies block the development of P. falciparum in mosquito membrane-feeding assays, illustrating the critical biological role of FREP1 during mosquito infection. We hypothesize that FREP1 expressed in An. gambiae and its binding partner(s) expressed in Plasmodium parasites can serve as novel, highly conserved TBV candidate antigens that limit Plasmodium infection in mammalian hosts and block transmission to the mosquito. To test this hypothesis, we have assembled a consortium of experts to identify the FREP1 binding partner(s) (FBPs) in Plasmodium parasites (Aim 1) and analyze the capacity of recombinant FREP1 and FBPs to serve as vaccine candidate antigens that limit Plasmodium infection in the mammalian hosts and block parasite development in mosquitoes (Aim 2). Successful completion of the proposed studies will determine novel vaccine targets for malaria control and reveal critical pathways of Plasmodium invasion in mosquito midguts.

描述（由适用提供）：疟原虫感染每年造成约2.5亿个疟疾临床病例，全世界近100万例死亡。疟原虫通过蚊子蚊子传播，其中蚊子是。冈比亚是非洲的主要载体。尽管在开发疟疾疫苗方面取得了进展，但针对肝脏和/或血液期寄生虫的当前策略不会阻止疾病传播。实际上，除非传播也被阻止，否则根除疟疾的长期目标将是不可能的。迄今为止，只有一项候选传输阻断疫苗（TBV）抗原（PFS25）已达到临床试验。但是，PFS25不能诱导跨物种阻塞（例如，恶性疟原虫和Vivax），并且不能完全阻断疟疾的传播。这是鉴定可以防止多种临床相关物质的疟原虫和增加阻塞效率传播的其他TBV抗原仍然是优先事项。该提案的目标是评估一种新型的，高度组成的蚊子表达的TBV疫苗候选抗原，并使用该分子来识别疟原虫寄生虫表达的其他TBV候选抗原。最近，我们报道了纤维蛋白原相关的蛋白-1（FREP1）在An中表达。冈比亚对于蚊子中的疟原虫感染是必需的。新的初步数据表明，FREP1蛋白质结合了啮齿动物berghei和人疟原虫感染的红细胞，这表明FREP1是蚊子中质量浸润高度保守的途径的一部分。重要的是，抗Frep1抗体阻止了蚊子喂养测定法中恶性疟原虫的发展，这说明了FREP1在蚊子感染过程中的关键生物学作用。我们假设在An中表达的FREP1。在疟原虫寄生虫中表达的冈比亚及其结合伴侣可以用作新型的高度组成的TBV候选抗原，这些抗原限制了哺乳动物宿主中疟原虫感染并将其阻塞到蚊子的传播。为了检验这一假设，我们已经组装了一个专家联盟，以识别疟原虫寄生虫中的FREP1结合伴侣（S）（FBP）（AIM 1），并分析重组FREP1和FBP的能力，以作为将疫苗候选抗原抗原抗原抗原的疟原虫感染的能力，以限制哺乳动物宿主的疟原虫感染的能力。成功完成拟议的研究将确定用于疟疾控制的新型疫苗靶标，并揭示蚊子中肠入侵的关键途径。