Targeting mosquito FREP1 protein for malaria control

 描述（由申请人提供）：疟原虫感染每年造成全球约2.5亿例疟疾临床病例和近100万例死亡。疟原虫是由按蚊传播的，其中按蚊。冈比亚是非洲的主要病媒。虽然在疟疾疫苗的开发方面取得了进展，但目前针对肝脏和/或血液阶段疟原虫寄生虫的战略不会阻止疾病的传播。事实上，如果不阻断传播，消灭疟疾的长期目标就不可能实现。迄今为止，只有一种候选传播阻断疫苗（TBV）抗原（Pfs 25）已进入临床试验。然而，Pfs 25不能诱导跨物种阻断（例如恶性疟原虫和间日疟原虫），并且它不能完全阻断疟疾传播。因此，鉴定可以防止多种临床相关疟原虫物种传播并增加阻断效力的其他TBV抗原仍然是优先事项。该提案的目标是评估一种新的、高度保守的蚊子表达的TBV疫苗候选抗原，并使用该分子来鉴定由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蛋白-1（FREP 1）在大肠杆菌中的表达。冈比亚是蚊子中疟原虫寄生虫感染所必需的。新的初步数据显示，FREP 1蛋白结合啮齿动物伯氏疟原虫和人类恶性疟原虫感染的红细胞，这表明FREP 1是疟原虫入侵蚊子的高度保守途径的一部分。重要的是，抗FREP 1抗体在蚊子膜摄食测定中阻断恶性疟原虫的发展，说明FREP 1在蚊子感染期间的关键生物学作用。我们推测FREP 1在An.冈比亚疟原虫及其在疟原虫寄生虫中表达的结合配偶体可作为新的高度保守的TBV候选抗原，其限制疟原虫在哺乳动物宿主中的感染并阻断传播至蚊子。为了验证这一假设，我们组建了一个专家联盟，以鉴定疟原虫寄生虫中的FREP 1结合伴侣（FBPs）（目标1），并分析重组FREP 1和FBPs作为疫苗候选抗原的能力，这些抗原限制了疟原虫在哺乳动物宿主中的感染，并阻断了疟原虫在蚊子中的发育（目标2）。成功完成拟议的研究将确定疟疾控制的新疫苗靶点，并揭示疟原虫入侵蚊子中肠的关键途径。

 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.