Unit of Insect Vector Genetics and Genomics, Department of Parasitology and Mycology, CNRS Unit URA 3012, Institut Pasteur, Paris, France.
PLoS One. 2012;7(12):e52684. doi: 10.1371/journal.pone.0052684. Epub 2012 Dec 28.
Functional studies have demonstrated a role for the Anopheles gambiae APL1A gene in resistance against the human malaria parasite, Plasmodium falciparum. Here, we exhaustively characterize the structure of the APL1 locus and show that three structurally different APL1A alleles segregate in the Ngousso colony. Genetic association combined with RNAi-mediated gene silencing revealed that APL1A alleles display distinct protective profiles against P. falciparum. One APL1A allele is sufficient to explain the protective phenotype of APL1A observed in silencing experiments. Epitope-tagged APL1A isoforms expressed in an in vitro hemocyte-like cell system showed that under assay conditions, the most protective APL1A isoform (APL1A(2)) localizes within large cytoplasmic vesicles, is not constitutively secreted, and forms only one protein complex, while a less protective isoform (APL1A(1)) is constitutively secreted in at least two protein complexes. The tested alleles are identical to natural variants in the wild A. gambiae population, suggesting that APL1A genetic variation could be a factor underlying natural heterogeneity of vector susceptibility to P. falciparum.
功能研究表明，冈比亚按蚊 APL1A 基因在抵抗人类疟原虫（Plasmodium falciparum）方面发挥作用。在这里，我们详尽地描述了 APL1 基因座的结构，并表明 Ngousso 群体中存在三种结构不同的 APL1A 等位基因。遗传关联与 RNAi 介导的基因沉默相结合表明，APL1A 等位基因对 P. falciparum 表现出不同的保护特征。一个 APL1A 等位基因足以解释在沉默实验中观察到的 APL1A 的保护表型。在体外类血细胞系统中表达的表位标记的 APL1A 同工型表明，在检测条件下，最具保护作用的 APL1A 同工型（APL1A(2)）定位于大细胞质囊泡内，不连续分泌，并且仅形成一种蛋白复合物，而保护作用较弱的同工型（APL1A(1)）至少以两种蛋白复合物形式连续分泌。所测试的等位基因与野生冈比亚按蚊群体中的天然变异相同，这表明 APL1A 遗传变异可能是蚊虫对 P. falciparum 易感性自然异质性的一个因素。
