A single full-length VAR2CSA ectodomain variant purifies broadly neutralizing antibodies against placental malaria isolates.
A single full-length VAR2CSA ectodomain variant purifies broadly neutralizing antibodies against placental malaria isolates.
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DOI：
10.7554/elife.76264
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发表时间：
2022-02-01
期刊：
影响因子：
7.7
通讯作者：
Duffy PE
中科院分区：
文献类型：
--
作者：
Doritchamou JYA;Renn JP;Jenkins B;Mahamar A;Dicko A;Fried M;Duffy PE
胎盘疟疾（PM）是一种致命的综合征，在第一次怀孕中最常见和严重。PM是由表达表面抗原VAR 2CSA并与胎盘中硫酸软骨素A（CSA）结合的恶性疟原虫感染的红细胞（IE）积累引起的。妇女在连续怀孕中变得对PM具有抵抗力，因为她们产生抗粘附和抗VAR 2CSA抗体，支持VAR 2CSA作为领先的PM候选疫苗。然而，第一种VAR 2CSA亚单位疫苗未能诱导广泛中和抗体，并且已知天然获得的抗体靶向变体特异性和保守表位。确定有效的疫苗是否需要掺入许多或仅单个VAR 2CSA变体至关重要。在此，在五种全长VAR 2CSA胞外域变体上依次纯化来自经产妇的IgG，从而耗尽IgG对每种的反应性。这五种VAR 2CSA变体纯化了约0.7%的总IgG，并对VAR 2CSA和IE表面抗原产生了菌株超越和菌株特异性反应性。在两个独立的抗体纯化/消耗实验中，VAR 2CSA变体的排列顺序，在第一个VAR 2CSA抗原上纯化的IgG显示出广泛的交叉反应性重组和天然VAR 2CSA变体，并抑制所有分离株与CSA的结合。与初始总IgG相比，在所有变体上耗尽后剩余的IgG显示出显著降低的结合抑制活性。这些发现表明，单个VAR 2CSA胞外域变体展示被多种寄生虫株（包括母体分离株）共有的中和（或结合抑制）抗体靶向的保守表位。这表明可以用有限数量的VAR 2CSA变体实现广泛有效的PM疫苗。怀孕期间感染疟疾-特别是第一次怀孕-可能导致严重的胎盘型疟疾，往往是致命的。感染疟疾寄生虫恶性疟原虫的红细胞显示出一种蛋白质VAR 2CSA，它可以识别并结合胎盘细胞和胎盘血液空间中存在的CSA分子。这会导致受感染的血细胞在胎盘中积聚并引起有害的炎症。在怀孕前接触过寄生虫会产生针对VAR 2CSA的抗体，阻止感染的血细胞附着在胎盘CSA上或标记它们进行免疫破坏。总的来说，这使得胎盘疟疾在随后的怀孕中不那么严重，并表明可以基于VAR 2CSA开发疫苗。然而，这种蛋白质具有可以在结构上变化的区域，这意味着恶性疟原虫可以产生许多VAR 2CSA变体。暴露于寄生虫的个体自然产生抗体，阻止各种变体附着于CSA。相比之下，基于VAR 2CSA片段的第一代疫苗仅诱导变体特异性抗体，因此提供有限的抗感染保护。作为回应，Doritchamou等人着手寻找可以被靶向一系列变体的抗体识别的VAR 2CSA结构。血液取自曾多次怀孕且对疟疾免疫的妇女。他们的血浆通过五种不同的大VAR 2CSA变体，以分离和纯化附着在这些结构上的抗体。Doritchamou等人发现，与单个VAR 2CSA结构结合的抗体也可以识别多种VAR 2CSA变体，并阻止所有测试的寄生虫粘附到CSA上。虽然还需要进一步的研究，但这些发现突出了与不同VAR 2CSA变体交叉反应的抗体，并可用于设计更有效的针对胎盘疟疾的疫苗。
Placental malaria (PM) is a deadly syndrome most frequent and severe in first pregnancies. PM results from accumulation of Plasmodium falciparum-infected erythrocytes (IE) that express the surface antigen VAR2CSA and bind to chondroitin sulfate A (CSA) in the placenta. Women become PM-resistant over successive pregnancies as they develop anti-adhesion and anti-VAR2CSA antibodies, supporting VAR2CSA as the leading PM-vaccine candidate. However, the first VAR2CSA subunit vaccines failed to induce broadly neutralizing antibody and it is known that naturally acquired antibodies target both variant-specific and conserved epitopes. It is crucial to determine whether effective vaccines will require incorporation of many or only a single VAR2CSA variants. Here, IgG from multigravidae was sequentially purified on five full-length VAR2CSA ectodomain variants, thereby depleting IgG reactivity to each. The five VAR2CSA variants purified ~0.7% of total IgG and yielded both strain-transcending and strain-specific reactivity to VAR2CSA and IE-surface antigen. In two independent antibody purification/depletion experiments with permutated order of VAR2CSA variants, IgG purified on the first VAR2CSA antigen displayed broad cross-reactivity to both recombinant and native VAR2CSA variants, and inhibited binding of all isolates to CSA. IgG remaining after depletion on all variants showed significantly reduced binding-inhibition activity compared to initial total IgG. These findings demonstrate that a single VAR2CSA ectodomain variant displays conserved epitopes that are targeted by neutralizing (or binding-inhibitory) antibodies shared by multiple parasite strains, including maternal isolates. This suggests that a broadly effective PM-vaccine can be achieved with a limited number of VAR2CSA variants. Contracting malaria during pregnancy – especially a first pregnancy – can lead to a severe, placental form of the disease that is often fatal. Red blood cells infected with the malaria parasite Plasmodium falciparum display a protein, VAR2CSA, which can recognize and bind CSA molecules present on placental cells and in placental blood spaces. This leads to the infected blood cells accumulating in the placenta and inducing harmful inflammation. Having been exposed to the parasite in prior pregnancies generates antibodies that target VAR2CSA, stopping the infected blood cells from latching onto placental CSA or tagging them for immune destruction. Overall, this makes placental malaria less severe in following pregnancies, and suggests that vaccines could be developed based on VAR2CSA. However, this protein has regions that can vary in structure, meaning that P. falciparaum can generate many VAR2CSA variants. Individuals exposed to the parasite naturally generate antibodies that block a wide array of variants from attaching to CSA. In contrast, first-generation vaccines based on VAR2CSA fragments have only induced variant-specific antibodies, therefore offering limited protection against infection. As a response, Doritchamou et al. set out to find VAR2CSA structures that could be recognized by antibodies targeting an array of variants. Blood was obtained from women who had had multiple pregnancies and were immune to malaria. Their plasma was passed over five different large VAR2CSA variants in order to isolate and purify antibodies that attached to these structures. Doritchamou et al. found that antibodies binding to individual VAR2CSA structures could also recognise a wide array of VAR2CSA variants and blocked all tested parasites from sticking to CSA. While further research is needed, these findings highlight antibodies that cross-react to diverse VAR2CSA variants and could be used to design more effective vaccines targeting placental malaria.
影响因子：
3.7
作者：
Tuikue Ndam N;Bischoff E;Proux C;Lavstsen T;Salanti A;Guitard J;Nielsen MA;Coppée JY;Gaye A;Theander T;David PH;Deloron P
通讯作者：
Deloron P