Targeting mosquito FREP1 protein for malaria control

 描述(申请人提供)：疟疾感染每年导致全球约2.5亿疟疾临床病例和近100万人死亡。疟原虫是通过按蚊传播的，其中一种是按蚊。冈比亚按蚊是非洲的主要媒介。尽管在开发疟疾疫苗方面取得了进展，但目前针对肝脏和/或血液阶段疟原虫的战略不会阻止疾病传播。事实上，除非传播也被阻断，否则根除疟疾的长期目标是不可能的。到目前为止，只有一个候选传播阻断疫苗(TBV)抗原(Pfs25)进入了临床试验。然而，Pfs25不能引起跨物种阻断(例如恶性疟原虫和间日疟原虫)，也不能完全阻断疟疾的传播。因此，确定更多的TBV抗原，以防止多种临床相关疟原虫的传播并增加阻断效果仍然是当务之急。这项建议的目的是评估一种新型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(FREP1)在胰腺癌中的表达。冈比亚是蚊子感染疟原虫所必需的。新的初步数据显示，FREP1蛋白与啮齿动物伯氏疟原虫和人类恶性疟原虫感染的红细胞结合，表明FREP1是恶性疟原虫入侵蚊子的高度保守途径的一部分。重要的是，抗FREP1抗体阻止了恶性疟原虫在蚊膜取食试验中的发育，说明了FREP1在蚊子感染过程中的关键生物学作用。我们推测FREP1在An.冈比亚原虫及其结合伙伴(S)可作为新型的高度保守的结核分枝杆菌候选抗原，限制疟原虫在哺乳动物宿主中的感染并阻断向蚊子的传播。为了验证这一假设，我们组建了一个专家联盟来鉴定疟原虫寄生虫中的FREP1结合伙伴(S)(FBPs)(目标1)，并分析重组FREP1和FBPs作为疫苗候选抗原的能力，以限制哺乳动物宿主中的疟疾感染并阻止蚊子中寄生虫的发展(目标2)。拟议研究的成功完成将确定疟疾控制的新疫苗目标，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.