ACE2 receptor expression and severe acute respiratory syndrome coronavirus infection depend on differentiation of human airway epithelia
ACE2 receptor expression and severe acute respiratory syndrome coronavirus infection depend on differentiation of human airway epithelia
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DOI：
10.1128/jvi.79.23.14614-14621.2005
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发表时间：
2005-12-01
影响因子：
5.4
通讯作者：
McCray, PB
中科院分区：
文献类型：
--
作者：
Jia, HP;Look, DC;McCray, PB
对严重急性呼吸综合征（SARS）患者的研究表明，呼吸道是SARS冠状病毒（CoV）感染和疾病发病的主要部位。我们研究了宿主-病原体的相互作用，使用天然肺组织和原代人气道上皮细胞的分化良好的培养物的模型。血管紧张素转换酶2（ACE 2）是SARS冠状病毒及其相关的人呼吸道冠状病毒NL 63的受体，在人气道上皮和肺实质中表达。通过免疫荧光染色和膜生物素化评估，ACE 2蛋白在极化的气道上皮的顶端比基底侧表面上表达更丰富。ACE 2的表达与上皮细胞的分化程度呈正相关。表达少量ACE 2的未分化细胞被SARS-CoV感染较差，而表达更多ACE 2的分化良好的细胞容易被感染。ACE 2在低分化上皮中的表达促进SARS刺突蛋白（S）-假型病毒进入。与ACE 2的表达模式一致，当应用于顶端表面时，SARS-CoV或用SARS-CoV S蛋白假型化的慢病毒进入分化的上皮细胞更有效。此外，SARS-CoV复制极化上皮细胞和优先退出通过顶端表面。结果表明，SARS冠状病毒对人气道上皮的感染与细胞分化状态以及ACE 2的表达和定位相关。这些发现对于理解与SARS-CoV和NL 63感染相关的疾病发病机制具有意义。
Studies of patients with severe acute respiratory syndrome (SARS) demonstrate that the respiratory tract is a major site of SARS-coronavirus (CoV) infection and disease morbidity. We studied host-pathogen interactions using native lung tissue and a model of well-differentiated cultures of primary human airway epithelia. Angiotensin converting enzyme 2 (ACE2), the receptor for both the SARS-CoV and the related human respiratory coronavirus NL63, was expressed in human airway epithelia as well as lung parenchyma. As assessed by immunofluorescence staining and membrane biotinylation, ACE2 protein was more abundantly expressed on the apical than the basolateral surface of polarized airway epithelia. Interestingly, ACE2 expression positively correlated with the differentiation state of epithelia. Undifferentiated cells expressing little ACE2 were poorly infected with SARS-CoV, while well-differentiated cells expressing more ACE2 were readily infected. Expression of ACE2 in poorly differentiated epithelia facilitated SARS spike (S) protein-pseudotyped virus entry. Consistent with the expression pattern of ACE2, the entry of SARS-CoV or a lentivirus pseudotyped with SARS-CoV S protein in differentiated epithelia was more efficient when applied to the apical surface. Furthermore, SARS-CoV replicated in polarized epithelia and preferentially exited via the apical surface. The results indicate that infection of human airway epithelia by SARS coronavirus correlates with the state of cell differentiation and ACE2 expression and localization. These findings have implications for understanding disease pathogenesis associated with SARS-CoV and NL63 infections.