Allelic polymorphisms in apical membrane antigen-1 are responsible for evasion of antibody-mediated inhibition in Plasmodium falciparum
Allelic polymorphisms in apical membrane antigen-1 are responsible for evasion of antibody-mediated inhibition in Plasmodium falciparum
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DOI：
10.1111/j.1365-2958.2003.03974.x
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发表时间：
2004-04-01
影响因子：
3.6
通讯作者：
Batchelor, A
中科院分区：
文献类型：
--
作者：
Healer, J;Murphy, V;Batchelor, A
顶膜抗原-1（AMA-1）是抑制恶性疟原虫侵入人红细胞的抗体的靶标，并且是包含在疟疾疫苗中的候选物。我们已经鉴定了对针对来自异源寄生虫系（3D 7）的蛋白质产生的抗AMA 1抗体较不敏感的恶性疟原虫系（W2 mef）。我们构建了表达异源AMA-1等位基因的转基因恶性疟原虫。体外侵袭试验表明，这些转基因寄生虫在对抑制性抗体的敏感性方面不同于亲本系，这提供了直接证据，即AMA-1内的序列多态性负责逃避抑制寄生虫侵袭的免疫应答。我们还产生了一个寄生虫线，将表达嵌合AMA-1蛋白，其中结构域1内的高度多态性残基交换。抑制试验表明，这些残基不足以抑制入侵阻断抗体。本研究首次利用恶性疟原虫等位基因交换来研究遗传多样性与保护性抗体易感性之间的关系。这些发现对开发基于AMA-1的疟疾疫苗具有重要意义。
Apical membrane antigen-1 (AMA-1) is a target of antibodies that inhibit invasion of Plasmodium falciparum into human erythrocytes and is a candidate for inclusion in a malaria vaccine. We have identified a line of P. falciparum (W2mef) less susceptible to anti-AMA1 antibodies raised to the protein from a heterologous parasite line (3D7). We have constructed transgenic P. falciparum expressing heterologous AMA-1 alleles. In vitro invasion assays show that these transgenic parasites differ from parental lines in susceptibility to inhibitory antibodies, providing direct evidence that sequence polymorphisms within AMA-1 are responsible for evasion of immune responses that inhibit parasite invasion. We also generated a parasite line that would express a chimeric AMA-1 protein, in which highly polymorphic residues within domain 1 were exchanged. Inhibition assays suggest that these residues are not sufficient for inhibition by invasion-blocking antibodies. This study is the first to use P. falciparum allelic exchange to examine the relationship between genetic diversity and susceptibility to protective antibodies. The findings have important implications for the development of an AMA-1-based malaria vaccine.