Protection against malaria after immunization by chloroquine prophylaxis and sporozoites is mediated by preerythrocytic immunity
Protection against malaria after immunization by chloroquine prophylaxis and sporozoites is mediated by preerythrocytic immunity
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DOI：
10.1073/pnas.1220360110
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发表时间：
2013-05-07
影响因子：
11.1
通讯作者：
Sauerwein, Robert W.
中科院分区：
文献类型：
--
作者：
Bijker, Else M.;Bastiaens, Guido J. H.;Sauerwein, Robert W.
在氯喹化学预防下用恶性疟原虫子孢子（CPS）免疫的志愿者发展针对同源子孢子攻击的完全的、持久的保护。氯喹既不影响子孢子，也不影响肝脏阶段，但一旦从肝脏释放到循环中，则仅杀死红细胞中的无性形式。因此，CPS免疫使宿主暴露于来自红细胞前和血液阶段的抗原，并且诱导的免疫可能靶向这些阶段中的任一个。因此，我们探讨了CPS诱导的保护的生命周期阶段特异性。25名疟疾初治志愿者参加了一项临床试验，其中15人接受了CPS免疫接种。5名免疫受试者和5名对照受试者通过蚊子叮咬接受子孢子攻击，而9名免疫受试者和5名对照受试者接受恶性疟原虫感染的红细胞的静脉内攻击。后一种方法完全绕过了红细胞前阶段，从而能够直接比较针对任一生命周期阶段的保护。CPS免疫的受试者（14例中的13例）产生了抗环子孢子抗体，而只有一名志愿者产生了针对典型血液阶段抗原的最低滴度。来自CPS免疫志愿者的IgG在体外不抑制无性血液阶段生长。所有CPS免疫的受试者（5/5）均受到子孢子攻击的保护。相比之下，九个CPS免疫的主题开发寄生虫血症后，血液阶段的挑战，具有相同的专利期和血液阶段的增殖率与对照组相比。与静脉内激发的对照相比，静脉内激发的CPS免疫的受试者表现出更早的发热和由IFN-γ诱导的炎性标志物D-二聚体、IFN-γ和单核因子的血浆浓度增加。完全缺乏对血液阶段攻击的保护表明，CPS诱导的保护是由对红细胞前阶段的免疫介导的。然而，有证据表明免疫识别恶性疟原虫感染的红细胞，提示记忆反应不能产生功能性免疫。
Volunteers immunized under chloroquine chemoprophylaxis with Plasmodium falciparum sporozoites (CPS) develop complete, long-lasting protection against homologous sporozoite challenge. Chloroquine affects neither sporozoites nor liver-stages, but kills only asexual forms in erythrocytes once released from the liver into the circulation. Consequently, CPS immunization exposes the host to antigens from both preerythrocytic and blood stages, and induced immunity might target either of these stages. We therefore explored the life cycle stage specificity of CPS-induced protection. Twenty-five malaria-nave volunteers were enrolled in a clinical trial, 15 of whom received CPS immunization. Five immunized subjects and five controls received a sporozoite challenge by mosquito bites, whereas nine immunized and five control subjects received an i.v. challenge with P. falciparum-infected erythrocytes. The latter approach completely bypasses preerythrocytic stages, enabling a direct comparison of protection against either life cycle stage. CPS-immunized subjects (13 of 14) developed anticircumsporozoite antibodies, whereas only one volunteer generated minimal titers against typical blood-stage antigens. IgG from CPS-immunized volunteers did not inhibit asexual blood-stage growth in vitro. All CPS-immunized subjects (5 of 5) were protected against sporozoite challenge. In contrast, nine of nine CPS-immunized subjects developed parasitemia after blood-stage challenge, with identical prepatent periods and blood-stage multiplication rates compared with controls. Intravenously challenged CPS-immunized subjects showed earlier fever and increased plasma concentrations of inflammatory markers D-dimer, IFN-gamma, and monokine induced by IFN-gamma than i.v. challenged controls. The complete lack of protection against blood-stage challenge indicates that CPS-induced protection is mediated by immunity against preerythrocytic stages. However, evidence is presented for immune recognition of P. falciparum-infected erythrocytes, suggesting memory responses unable to generate functional immunity.