CX3CR1 Is Expressed in Differentiated Human Ciliated Airway Cells and Co-Localizes with Respiratory Syncytial Virus on Cilia in a G Protein-Dependent Manner

Respiratory syncytial virus (RSV) is the principal cause of bronchiolitis in infants and a significant healthcare problem. The RSV Glycoprotein (G) mediates attachment of the virus to the cell membrane, which facilitates interaction of the RSV Fusion (F) protein with nucleolin, thereby triggering fusion of the viral and cellular membranes. However, a host protein ligand for G has not yet been identified. Here we show that CX3CR1 is expressed in the motile cilia of differentiated human airway epithelial (HAE) cells, and that CX3CR1 co-localizes with RSV particles. Upon infection, the distribution of CX3CR1 in these cells is significantly altered. Complete or partial deletion of RSV G results in viruses binding at least 72-fold less efficiently to cells, and reduces virus replication. Moreover, an antibody targeting an epitope near the G protein’s CX3CR1-binding motif significantly inhibits binding of the virus to airway cells. Given previously published evidence of the interaction of G with CX3CR1 in human lymphocytes, these findings suggest a role for G in the interaction of RSV with ciliated lung cells. This interpretation is consistent with past studies showing a protective benefit in immunizing against G in animal models of RSV infection, and would support targeting the CX3CR1-G protein interaction for prophylaxis or therapy. CX3CR1 expression in lung epithelial cells may also have implications for other respiratory diseases such as asthma.

呼吸道合胞病毒（Respiratory syncytial virus, RSV）是引发婴幼儿细支气管炎的主要病原体，亦是一项重大的公共卫生难题。RSV糖蛋白G（RSV Glycoprotein, G）可介导病毒黏附于宿主细胞膜，该过程能够促进RSV融合（Fusion, F）蛋白与核仁素的相互作用，进而触发病毒包膜与细胞膜的融合。然而，目前尚未发现针对G蛋白的宿主蛋白配体。
本研究证实，C-X3-C趋化因子受体1（CX3CR1）在分化成熟的人气道上皮（HAE）细胞的运动纤毛中表达，且CX3CR1与RSV病毒颗粒存在共定位现象。感染发生后，CX3CR1在这类细胞中的分布会发生显著改变。
对RSV G蛋白进行完全或部分敲除后，病毒与细胞的结合效率至少降低72倍，同时病毒的复制能力也会减弱。此外，靶向G蛋白CX3CR1结合基序附近表位的抗体，可显著抑制病毒与气道细胞的结合。
结合此前已发表的关于G蛋白与CX3CR1在人类淋巴细胞中相互作用的研究证据，本研究结果表明G蛋白在RSV与纤毛肺细胞的相互作用中发挥了重要功能。该结论与此前在RSV感染动物模型中开展的免疫接种G蛋白可产生保护作用的研究结果一致，同时也支持将靶向CX3CR1-G蛋白相互作用作为预防或治疗策略。此外，CX3CR1在肺上皮细胞中的表达，或许还与哮喘等其他呼吸道疾病存在潜在关联。