Lavazec C, Boudin C, Lacroix R, Bonnet S, Diop A, Thiberge S, Boisson B, Tahar R, Bourgouin C
Unité de Biologie et Génétique du Paludisme, Institut Pasteur, 25 rue du Dr Roux, 75015 Paris, France.
Infect Immun. 2007 Apr;75(4):1635-42. doi: 10.1128/IAI.00864-06. Epub 2007 Feb 5.
Anopheles gambiae is the major African vector of Plasmodium falciparum, the most deadly species of human malaria parasite and the most prevalent in Africa. Several strategies are being developed to limit the global impact of malaria via reducing transmission rates, among which are transmission-blocking vaccines (TBVs), which induce in the vertebrate host the production of antibodies that inhibit parasite development in the mosquito midgut. So far, the most promising components of a TBV are parasite-derived antigens, although targeting critical mosquito components might also successfully block development of the parasite in its vector. We previously identified A. gambiae genes whose expression was modified in P. falciparum-infected mosquitoes, including one midgut carboxypeptidase gene, cpbAg1. Here we show that P. falciparum up-regulates the expression of cpbAg1 and of a second midgut carboxypeptidase gene, cpbAg2, and that this up-regulation correlates with an increased carboxypeptidase B (CPB) activity at a time when parasites establish infection in the mosquito midgut. The addition of antibodies directed against CPBAg1 to a P. falciparum-containing blood meal inhibited CPB activity and blocked parasite development in the mosquito midgut. Furthermore, the development of the rodent parasite Plasmodium berghei was significantly reduced in mosquitoes fed on infected mice that had been immunized with recombinant CPBAg1. Lastly, mosquitoes fed on anti-CPBAg1 antibodies exhibited reduced reproductive capacity, a secondary effect of a CPB-based TBV that could likely contribute to reducing Plasmodium transmission. These results indicate that A. gambiae CPBs could constitute targets for a TBV that is based upon mosquito molecules.
冈比亚按蚊是非洲传播恶性疟原虫的主要媒介，恶性疟原虫是人类疟疾寄生虫中最致命的种类，也是非洲最普遍的疟原虫。目前正在开发多种策略，通过降低传播率来限制疟疾对全球的影响，其中包括传播阻断疫苗（TBV），这种疫苗可在脊椎动物宿主中诱导产生抗体，抑制疟原虫在蚊子中肠内的发育。到目前为止，TBV最有前景的成分是源自疟原虫的抗原，不过靶向关键的蚊子成分也可能成功阻断疟原虫在其媒介中的发育。我们之前鉴定出了冈比亚按蚊中那些在感染恶性疟原虫的蚊子中表达发生改变的基因，其中包括一个中肠羧肽酶基因cpbAg1。在此我们表明，恶性疟原虫会上调cpbAg1以及另一个中肠羧肽酶基因cpbAg2的表达，而且这种上调与疟原虫在蚊子中肠建立感染时羧肽酶B（CPB）活性的增加相关。向含有恶性疟原虫的血餐中添加针对CPBAg1的抗体，会抑制CPB活性，并阻断疟原虫在蚊子中肠内的发育。此外，在以用重组CPBAg1免疫过的感染小鼠为食的蚊子中，啮齿动物疟原虫伯氏疟原虫的发育显著减少。最后，以抗CPBAg1抗体为食的蚊子生殖能力降低，这是基于CPB的TBV的一种次要效应，可能有助于减少疟原虫的传播。这些结果表明，冈比亚按蚊CPB可能构成基于蚊子分子的TBV的靶点。
