Boyle Michelle J, Reiling Linda, Feng Gaoqian, Langer Christine, Osier Faith H, Aspeling-Jones Harvey, Cheng Yik Sheng, Stubbs Janine, Tetteh Kevin K A, Conway David J, McCarthy James S, Muller Ivo, Marsh Kevin, Anders Robin F, Beeson James G
The Burnet Institute for Medical Research and Public Health, 85 Commercial Road, Melbourne, VIC 3004, Australia; Department of Medical Biology, University of Melbourne, Royal Parade, Melbourne, VIC 3010, Australia.
The Burnet Institute for Medical Research and Public Health, 85 Commercial Road, Melbourne, VIC 3004, Australia.
Immunity. 2015 Mar 17;42(3):580-90. doi: 10.1016/j.immuni.2015.02.012.
Antibodies play major roles in immunity to malaria; however, a limited understanding of mechanisms mediating protection is a major barrier to vaccine development. We have demonstrated that acquired human anti-malarial antibodies promote complement deposition on the merozoite to mediate inhibition of erythrocyte invasion through C1q fixation and activation of the classical complement pathway. Antibody-mediated complement-dependent (Ab-C') inhibition was the predominant invasion-inhibitory activity of human antibodies; most antibodies were non-inhibitory without complement. Inhibitory activity was mediated predominately via C1q fixation, and merozoite surface proteins 1 and 2 were identified as major targets. Complement fixation by antibodies was very strongly associated with protection from both clinical malaria and high-density parasitemia in a prospective longitudinal study of children. Ab-C' inhibitory activity could be induced by human immunization with a candidate merozoite surface-protein vaccine. Our findings demonstrate that human anti-malarial antibodies have evolved to function by fixing complement for potent invasion-inhibitory activity and protective immunity.
抗体在疟疾免疫中发挥着主要作用；然而，对介导保护作用的机制了解有限是疫苗开发的主要障碍。我们已经证明，获得性人类抗疟抗体可促进补体在裂殖子上沉积，通过C1q固定和经典补体途径的激活来介导对红细胞入侵的抑制。抗体介导的补体依赖性（Ab-C'）抑制是人类抗体主要的入侵抑制活性；大多数抗体在没有补体的情况下无抑制作用。抑制活性主要通过C1q固定介导，裂殖子表面蛋白1和2被确定为主要靶点。在一项针对儿童的前瞻性纵向研究中，抗体介导的补体固定与预防临床疟疾和高密度寄生虫血症密切相关。用候选裂殖子表面蛋白疫苗对人类进行免疫可诱导Ab-C'抑制活性。我们的研究结果表明，人类抗疟抗体已进化为通过固定补体来发挥作用，从而产生强大的入侵抑制活性和保护性免疫。
