A conserved multi-gene family induces cross-reactive antibodies effective in defense against Plasmodium falciparum.
A conserved multi-gene family induces cross-reactive antibodies effective in defense against Plasmodium falciparum.
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DOI：
10.1371/journal.pone.0005410
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发表时间：
2009
期刊：
影响因子：
3.7
通讯作者：
Druilhe P
中科院分区：
文献类型：
--
作者：
Singh S;Soe S;Weisman S;Barnwell JW;Pérignon JL;Druilhe P
两个相关的裂殖子表面蛋白，MSP 3和MSP 6，以前已被确定为抗体依赖性细胞抑制（ADCI），对恶性疟原虫疟疾的保护机制的目标。MSP 3和MSP 6都有一个共同的特征性小N端签名氨基酸段（NLRNA/G），这一特征类似于在其他人类和灵长类疟疾寄生虫中鉴定的MSP 3样直系同源物。这个标志性的氨基酸序列导致鉴定出8个连续位于恶性疟原虫10号染色体上的ORF。我们随后的研究，其表达，定位，序列保守性，表位共享，免疫原性和抗体在防御中的功能作用在这里报告。恶性疟原虫MSP 3多基因家族的6个成员在其C-末端区域内具有相似的序列结构，同时表达为裂殖子表面蛋白，并且在寄生虫分离株中高度保守。这些蛋白质中的每一种都是在ADCI测定中有效杀死寄生虫的天然存在的抗体的靶标。此外，天然存在的抗体和通过免疫产生的抗体都显示出与家族其他成员的交叉反应性，并表现出不同的结合亲和力。MSP 3多基因家族的不寻常特征使我们假设，同时表达的靶点引发交叉反应性抗体反应，能够控制寄生虫密度可能代表了通过进化选择的免疫过程，以维持恶性疟原虫和人类宿主之间的稳态;一个过程，允许寄生虫的连续传播而不杀死宿主。我们的观察结果还对疫苗开发具有实际影响，表明当与MSP 3家族成员的各种C-末端区域组合以产生更广泛的抗体作用并增加疫苗在不同人类遗传背景中的免疫原性时，MSP 3疫苗功效可能会得到改善。
Two related merozoite surface proteins, MSP3 and MSP6, have previously been identified as targets of antibody-dependent cellular inhibition (ADCI), a protective mechanism against Plasmodium falciparum malaria. Both MSP3 and MSP6 share a common characteristic small N-terminal signature amino-acid stretch (NLRNA/G), a feature similar to MSP3-like orthologs identified in other human and primate malaria parasites. This signature amino-acid sequence led to the identification of eight ORFs contiguously located on P. falciparum chromosome 10. Our subsequent investigations on their expression, localization, sequence conservation, epitope sharing, immunogenicity and the functional role of antibodies in defense are reported here. Six members of P. falciparum MSP3-multigene family share similar sequence organization within their C-terminal regions, are simultaneously expressed as merozoite surface proteins and are highly conserved among parasite isolates. Each of these proteins is a target of naturally occurring antibodies effective at parasite killing in ADCI assays. Moreover, both naturally occurring antibodies and those generated by immunization display cross-reactivity with other members of the family and exhibit varied binding avidities. The unusual characteristics of the MSP3 multi-gene family lead us to hypothesize that the simultaneous expression of targets eliciting cross-reactive antibody responses capable of controlling parasite densities could represent an immune process selected through evolution to maintain homeostasis between P. falciparum and human hosts; a process that allows the continuous transmission of the parasite without killing the host. Our observations also have practical consequences for vaccine development by suggesting MSP3 vaccine efficacy might be improved when combined with the various C-terminus regions of the MSP3 family members to generate a wider range of antibodies acting and to increase vaccine immunogenicity in varied human genetic backgrounds.
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影响因子：
2.2
作者：
Osier FH;Polley SD;Mwangi T;Lowe B;Conway DJ;Marsh K
通讯作者：
Marsh K
影响因子：
64.8
作者：
Carlton, Jane M.;Adams, John H.;Silva, Joana C.;Bidwell, Shelby L.;Lorenzi, Hernan;Caler, Elisabet;Crabtree, Jonathan;Angiuoli, Samuel V.;Merino, Emilio F.;Amedeo, Paolo;Cheng, Qin;Coulson, Richard M. R.;Crabb, Brendan S.;del Portillo, Hernando A.;Essien, Kobby;Feldblyum, Tamara V.;Fernandez-Becerra, Carmen;Gilson, Paul R.;Gueye, Amy H.;Guo, Xiang;Kang'a, Simon;Kooij, Taco W. A.;Korsinczky, Michael;Meyer, Esmeralda V. -S.;Nene, Vish;Paulsen, Ian;White, Owen;Ralph, Stuart A.;Ren, Qinghu;Sargeant, Tobias J.;Salzberg, Steven L.;Stoeckert, Christian J.;Sullivan, Steven A.;Yamamoto, Marcio M.;Hoffman, Stephen L.;Wortman, Jennifer R.;Gardner, Malcolm J.;Galinski, Mary R.;Barnwell, John W.;Fraser-Liggett, Claire M.
通讯作者：
Fraser-Liggett, Claire M.
影响因子：
15.8
作者：
Druilhe P;Spertini F;Soesoe D;Corradin G;Mejia P;Singh S;Audran R;Bouzidi A;Oeuvray C;Roussilhon C
通讯作者：
Roussilhon C
影响因子：
3.6
作者：
Mills, KE;Pearce, JA;Cowman, AF
通讯作者：
Cowman, AF
影响因子：
1.5
作者：
Kaneko, O;Fidock, DA;Miller, LH
通讯作者：
Miller, LH