Division of Parasitology, MRC National Institute for Medical Research, Mill Hill, London, United Kingdom.
Infect Immun. 2012 Mar;80(3):1280-7. doi: 10.1128/IAI.05887-11. Epub 2011 Dec 27.
Merozoite surface protein 1 (MSP1) is a target for malaria vaccine development. Antibodies to the 19-kDa carboxy-terminal region referred to as MSP1(19) inhibit erythrocyte invasion and parasite growth, with some MSP1-specific antibodies shown to inhibit the proteolytic processing of MSP1 that occurs at invasion. We investigated a series of antibodies purified from rabbits immunized with MSP1(19) and AMA1 recombinant proteins for their ability to inhibit parasite growth, initially looking at MSP1 processing. Although significant inhibition of processing was mediated by several of the antibody samples, there was no clear relationship with overall growth inhibition by the same antibodies. However, no antibody samples inhibited processing but not invasion, suggesting that inhibition of MSP1 processing contributes to but is not the only mechanism of antibody-mediated inhibition of invasion and growth. Examining other mechanisms by which MSP1-specific antibodies inhibit parasite growth, we show that MSP1(19)-specific antibodies are taken up into invaded erythrocytes, where they persist for significant periods and result in delayed intracellular parasite development. This delay may result from antibody interference with coalescence of MSP1(19)-containing vesicles with the food vacuole. Antibodies raised against a modified recombinant MSP1(19) sequence were more efficient at delaying intracellular growth than those to the wild-type protein. We propose that antibodies specific for MSP1(19) can mediate inhibition of parasite growth by at least three mechanisms: inhibition of MSP1 processing, direct inhibition of invasion, and inhibition of parasite development following invasion. The balance between mechanisms may be modulated by modifying the immunogen used to induce the antibodies.
裂殖子表面蛋白 1（MSP1）是疟疾疫苗开发的靶标。针对 19kDa 羧基末端区域的抗体（称为 MSP1（19））可抑制红细胞入侵和寄生虫生长，一些 MSP1 特异性抗体已被证明可抑制入侵时 MSP1 的蛋白水解加工。我们研究了一系列从用 MSP1（19）和 AMA1 重组蛋白免疫的兔子中纯化的抗体，以评估它们抑制寄生虫生长的能力，最初着眼于 MSP1 加工。尽管几种抗体样本可显著抑制加工，但与相同抗体的总体生长抑制之间没有明确的关系。然而，没有抗体样本抑制加工但不抑制入侵，这表明抑制 MSP1 加工有助于但不是抗体介导的入侵和生长抑制的唯一机制。研究 MSP1 特异性抗体抑制寄生虫生长的其他机制时，我们表明 MSP1（19）特异性抗体被摄取到入侵的红细胞中，在那里它们持续存在很长时间，并导致细胞内寄生虫发育延迟。这种延迟可能是由于抗体干扰了含有 MSP1（19）的囊泡与食物泡的融合。针对经过修饰的重组 MSP1（19）序列产生的抗体比针对野生型蛋白的抗体更有效地延迟细胞内生长。我们提出，针对 MSP1（19）的抗体可以通过至少三种机制介导对寄生虫生长的抑制：抑制 MSP1 加工、直接抑制入侵以及入侵后抑制寄生虫发育。用于诱导抗体的免疫原的修饰可能会调节机制之间的平衡。
