Genetic Evidence for Erythrocyte Receptor Glycophorin B Expression Levels Defining a Dominant Plasmodium falciparum Invasion Pathway into Human Erythrocytes.
Genetic Evidence for Erythrocyte Receptor Glycophorin B Expression Levels Defining a Dominant Plasmodium falciparum Invasion Pathway into Human Erythrocytes.
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DOI：
10.1128/iai.00074-17
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发表时间：
2017-10
影响因子：
3.1
通讯作者：
Duraisingh MT
中科院分区：
文献类型：
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作者：
Dankwa S;Chaand M;Kanjee U;Jiang RHY;Nobre LV;Goldberg JM;Bei AK;Moechtar MA;Grüring C;Ahouidi AD;Ndiaye D;Dieye TN;Mboup S;Weekes MP;Duraisingh MT
恶性疟原虫是导致最致命形式的疟疾的寄生虫，它已经进化出多种被称为入侵配体的蛋白质，这些蛋白质与特定的红细胞受体结合，促进对人类红细胞的入侵。EBA-175/glycophorin A （GPA）和Rh5/basigin配体-受体相互作用被称为入侵途径，一直是研究的热点。在这项研究中，我们重点研究了较少表征的含唾液酸受体糖蛋白B （GPB）和糖蛋白C （GPC）。通过生物信息学分析，我们发现贝宁个体中糖蛋白B （GYPB）转录物水平存在广泛差异，这表明来自疟疾压力的选择。为了阐明GPB和GPC受体相对于EBA-175/GPA侵袭途径的重要性，我们使用离体红细胞培养系统，通过红细胞祖细胞的慢病毒短发卡RNA转导来降低GPA、GPB或GPC的表达，并进行了全球表面蛋白质组学分析。我们使用一组野生型恶性疟原虫实验室菌株和入侵配体敲除系，以及塞内加尔恶性疟原虫临床分离株和短期培养适应株，评估了寄生虫侵入敲除细胞的效率。为此，我们优化了一种适合少量红细胞使用的侵袭试验。我们发现所有实验室菌株和大部分野外菌株都依赖于GPB表达水平进行侵袭。集体数据表明，GPA和GPB受体比GPC受体更重要，支持恶性疟原虫红细胞受体使用的层次结构。
Plasmodium falciparum, the parasite that causes the deadliest form of malaria, has evolved multiple proteins known as invasion ligands that bind to specific erythrocyte receptors to facilitate invasion of human erythrocytes. The EBA-175/glycophorin A (GPA) and Rh5/basigin ligand-receptor interactions, referred to as invasion pathways, have been the subject of intense study. In this study, we focused on the less-characterized sialic acid-containing receptors glycophorin B (GPB) and glycophorin C (GPC). Through bioinformatic analysis, we identified extensive variation in glycophorin B (GYPB) transcript levels in individuals from Benin, suggesting selection from malaria pressure. To elucidate the importance of the GPB and GPC receptors relative to the well-described EBA-175/GPA invasion pathway, we used an ex vivo erythrocyte culture system to decrease expression of GPA, GPB, or GPC via lentiviral short hairpin RNA transduction of erythroid progenitor cells, with global surface proteomic profiling. We assessed the efficiency of parasite invasion into knockdown cells using a panel of wild-type P. falciparum laboratory strains and invasion ligand knockout lines, as well as P. falciparum Senegalese clinical isolates and a short-term-culture-adapted strain. For this, we optimized an invasion assay suitable for use with small numbers of erythrocytes. We found that all laboratory strains and the majority of field strains tested were dependent on GPB expression level for invasion. The collective data suggest that the GPA and GPB receptors are of greater importance than the GPC receptor, supporting a hierarchy of erythrocyte receptor usage in P. falciparum.