A genetic approach to the de novo identification of targets of strain-specific immunity in malaria parasites
A genetic approach to the de novo identification of targets of strain-specific immunity in malaria parasites
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DOI：
10.1073/pnas.0405097102
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发表时间：
2005-01-18
影响因子：
11.1
通讯作者：
Carter, R
中科院分区：
文献类型：
--
作者：
Martinelli, A;Cheesman, S;Carter, R
疟疾疫苗研究具有很高的优先地位。然而，确定特定抗原作为针对疟疾寄生虫无性血液期疫苗的候选者主要是基于间接证据。我们在这里描述了编码疟疾菌株特异性免疫的靶抗原的基因如何通过我们称为连锁组选择的方法直接定位在寄生虫的基因组中，而不需要关于其身份的先验信息。两个不同的啮齿动物疟疾寄生虫查鲍迪疟原虫的基因克隆被基因杂交，每个克隆在实验室小鼠中诱导的免疫力比与异源品系相比更能抵御自身的攻击，而未克隆的杂交后代是在通过感染和用一种或另一种亲本菌株的药物治疗而部分免疫的小鼠中选择的。利用全基因组分子标记技术比较了杂交后代中亲本等位基因的比例。一小部分，包括形成所谓选择谷的连锁标记组，在菌株特异性免疫压力下显著减少。一个非常显著的选择谷被发现包含裂殖子表面蛋白-1的基因，裂殖子表面蛋白-1是疟疾疫苗开发的主要候选抗原，在菌株特异性免疫选择下检测到最强的减少。与裂殖子表面蛋白-1基因紧密连锁的是一个含有环状感染红细胞表面抗原家族特征基序的基因。另一个受影响的基因座与这个选择谷无关，包含丝氨酸重复抗原基因家族的一个成员。
Vaccine research in malaria has a high priority. However, identification of specific antigens as candidates for vaccines against asexual blood stages of malaria parasites has been based on largely circumstantial evidence. We describe here how genes encoding target antigens of strain-specific immunity in malaria can be directly located in the parasite's genome without prior information concerning their identity, by the method we call linkage group selection. Two genetically distinct clones of the rodent malaria parasite Plasmodium chabaudi chabaudi, each of which induces an immunity in laboratory mice that is more protective against challenge with itself than with the heterologous strain, were genetically crossed, and the uncloned cross progeny selected in mice that had been made partially immune by infection and drug cure with one or the other parental strain. Proportions of parental alleles in the selected and unselected cross progeny were compared by using quantitative genome-wide molecular markers. A small number, including groups of linked markers forming so-called selection valleys, were markedly reduced under strain-specific immune pressure. A very prominent selection valley was found to contain the gene for merozoite surface protein-1, a major candidate antigen for malaria vaccine development, at the locus at which the strongest reduction under strain-specific immune selection was detected. Closely linked to the merozoite surface protein-1 gene was a gene containing the signature motif of the ring-infected erythrocyte surface antigen family. Another affected locus, unlinked to this selection valley, contained a member of the serine repeat antigen gene family.