Measles virus blind to its epithelial cell receptor remains virulent in rhesus monkeys but cannot cross the airway epithelium and is not shed
Measles virus blind to its epithelial cell receptor remains virulent in rhesus monkeys but cannot cross the airway epithelium and is not shed
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DOI：
10.1172/jci35454
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发表时间：
2008-07-01
影响因子：
15.9
通讯作者：
Cattaneo, Roberto
中科院分区：
文献类型：
--
作者：
Leonard, Vincent H. J.;Sinn, Patrick L.;Cattaneo, Roberto
麻疹病毒（MV）的发病机制的现有模型表明，气道上皮细胞的顶端感染先于全身传播。另一种模型表明，主要感染的淋巴细胞携带MV到上皮细胞的基底外侧表面，支持MV脱落到气道腔和传染。该模型预测，不能通过未鉴定的上皮细胞受体（EpR）进入细胞的突变MV将保持毒性，但不会脱落。为了测试这个模型，我们确定了MV附着蛋白的残基维持EpR介导的细胞融合。这些非极性或不带电荷的极性残基限定了位于信号淋巴细胞活化分子（SLAM）（淋巴细胞上MV的受体）的结合位点附近的区域。然后，我们产生了EpR盲病毒维持SLAM依赖的细胞进入和接种恒河猴鼻内。选择性EpR-bhnd MV感染的宿主出现皮疹和厌食症，同时平均病毒血症略低于野生型MV感染的宿主，但不会在气道中散发病毒。使用原代分化良好的人气道上皮细胞表征限制脱落的机制。野生型MV感染的柱状上皮细胞轴承紧密连接时，只有应用basolatively，而EpR盲病毒没有感染这些细胞。因此，EpR可能是一种基底外侧蛋白，并且气道上皮的感染对于MV的全身传播和毒力不是必需的。
The current model of measles virus (MV) pathogenesis implies that apical infection of airway epithelial cells precedes systemic spread. An alternative model suggests that primarily infected lymphatic cells carry MV to the basolateral surface of epithelial cells, supporting MV shedding into the airway lumen and contagion. This model predicts that a mutant MV, unable to enter cells through the unidentified epithelial cell receptor (EpR), would remain virulent but not be shed. To test this model, we identified residues of the MV attachment protein sustaining EpR-mediated cell fusion. These nonpolar or uncharged polar residues defined an area located near the binding site of the signaling lymphocytic activation molecule (SLAM), the receptor for MV on lymphatic cells. We then generated an EpR-blind virus maintaining SLAM-dependent cell entry and inoculated rhesus monkeys intranasally. Hosts infected with the selectively EpR-bhnd MV developed rash and anorexia while averaging slightly lower viremia than hosts infected with wild-type MV but did not shed virus in the airways. The mechanism restricting shedding was characterized using primary well-differentiated human airway epithelial cells. Wild-type MV infected columnar epithelial cells bearing tight junctions only when applied basolaterally, while the EpR-blind virus did not infect these cells. Thus, EpR is probably a basolateral protein, and infection of the airway epithelium is not essential for systemic spread and virulence of MV.