Experimental adaptation of wild-type canine distemper virus (CDV) to the human entry receptor CD150.
Experimental adaptation of wild-type canine distemper virus (CDV) to the human entry receptor CD150.
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DOI：
10.1371/journal.pone.0057488
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发表时间：
2013
期刊：
影响因子：
3.7
通讯作者：
Schneider-Schaulies J
中科院分区：
文献类型：
--
作者：
Bieringer M;Han JW;Kendl S;Khosravi M;Plattet P;Schneider-Schaulies J
犬瘟热病毒（CDV）是麻疹病毒（MV）的近亲，以其广泛的宿主范围而闻名。当消灭麻疹的目标可能实现，当麻疹疫苗接种将被停止时，CDV可能最终跨越物种屏障进入人类，并作为一种新的人类病原体出现。为了了解这种改变发生的速度有多快，我们对人类进入受体CD150 （SLAM）和连接素-4的适应性突变进行了表征，作为感染人类靶细胞的第一步。重组野生型CDV-A75/17red在表达人连接素-4的人H358上皮细胞中快速适应生长。病毒附着蛋白（血凝素H和融合蛋白F）基因的测序显示，利用人类连接蛋白4不需要适应性改变。相反，病毒在表达人CD150 （Vero- hslam）的Vero细胞中只复制到低滴度（102 pfu/ml）。经过三次传代后，这些细胞使病毒适应于人CD150并复制到高滴度（105 pfu/ml）。序列分析表明，h蛋白在540 Asp→Gly （D540G）位置上只需要一个氨基酸交换就能实现对人类CD150的功能适应。结构模型分析表明，H中的适应性突变D540G反映了从犬到人的CD150在70和71号位置从Pro到Leu （P70L）和Gly到Glu （G71E）的序列变化，并补偿了人类CD150分子中负电荷的增加。使用这个模型系统，我们的数据表明，CDV对人类进入受体的适应只需要一个最小的改变，在这种情况下，一个适应性突变，并有助于理解这种适应性突变发生的分子基础。
Canine distemper virus (CDV), a close relative of measles virus (MV), is widespread and well known for its broad host range. When the goal of measles eradication may be achieved, and when measles vaccination will be stopped, CDV might eventually cross the species barrier to humans and emerge as a new human pathogen. In order to get an impression how fast such alterations may occur, we characterized required adaptive mutations to the human entry receptors CD150 (SLAM) and nectin-4 as first step to infect human target cells. Recombinant wild-type CDV-A75/17red adapted quickly to growth in human H358 epithelial cells expressing human nectin-4. Sequencing of the viral attachment proteins (hemagglutinin, H, and fusion protein, F) genes revealed that no adaptive alteration was required to utilize human nectin-4. In contrast, the virus replicated only to low titres (102 pfu/ml) in Vero cells expressing human CD150 (Vero-hSLAM). After three passages using these cells virus was adapted to human CD150 and replicated to high titres (105 pfu/ml). Sequence analyses revealed that only one amino acid exchange in the H-protein at position 540 Asp→Gly (D540G) was required for functional adaptation to human CD150. Structural modelling suggests that the adaptive mutation D540G in H reflects the sequence alteration from canine to human CD150 at position 70 and 71 from Pro to Leu (P70L) and Gly to Glu (G71E), and compensates for the gain of a negative charge in the human CD150 molecule. Using this model system our data indicate that only a minimal alteration, in this case one adaptive mutation, is required for adaptation of CDV to the human entry receptors, and help to understand the molecular basis why this adaptive mutation occurs.
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