Comparative biology of rAAV transduction in ferret, pig and human airway epithelia
Comparative biology of rAAV transduction in ferret, pig and human airway epithelia
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DOI：
10.1038/sj.gt.3303014
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发表时间：
2007-11-01
期刊：
影响因子：
5.1
通讯作者：
Engelhardt, J. F.
中科院分区：
文献类型：
--
作者：
Liu, X.;Luo, M.;Engelhardt, J. F.
啮齿动物和人类气道细胞生物学之间的差异使得难以将重组腺相关病毒（rAAV）介导的基因疗法翻译到肺用于囊性纤维化（CF）。随着新的雪貂和猪CF模型的出现，关于这些物种中宿主细胞/载体相互作用的知识对于测试潜在的基因疗法将变得越来越重要。为此，我们比较了三种rAAV血清型（AAV 1、2和5）在人、雪貂、猪和小鼠极化气道上皮中的转导生物学。我们的结果表明，用这些rAAV血清型对雪貂和猪气道上皮细胞的顶端转导与在人上皮细胞中观察到的情况（rAAV 1> rAAV 2与rAAV 5一致）密切对应，而小鼠上皮细胞的转导显著不同（rAAV 1> rAAV 5>= rAAV 2）。类似地，雪貂、猪和人上皮细胞也在rAAV转导的极性（顶侧vs基底侧）和蛋白酶体依赖性方面具有共同的亚型特异性差异。尽管有这些相似之处，N-连接的唾液酸受体需要rAAV 1和rAAV 5转导的人和小鼠气道上皮细胞，但不是雪貂或猪气道上皮细胞。因此，尽管与小鼠相比，rAAV血清型1、2和5的气道嗜性在雪貂、猪和人中更好地保守，但病毒受体/共受体似乎保持了相当大的物种多样性。
Differences between rodent and human airway cell biology have made it difficult to translate recombinant adeno-associated virus (rAAV)-mediated gene therapies to the lung for cystic fibrosis (CF). As new ferret and pig models for CF become available, knowledge about host cell/ vector interactions in these species will become increasingly important for testing potential gene therapies. To this end, we have compared the transduction biology of three rAAV serotypes (AAV1, 2 and 5) in human, ferret, pig and mouse- polarized airway epithelia. Our results indicate that apical transduction of ferret and pig airway epithelia with these rAAV serotypes closely mirrors that observed in human epithelia (rAAV1 > rAAV2 congruent to rAAV5), while transduction of mouse epithelia was significantly different (rAAV1 > rAAV5 >= rAAV2). Similarly, ferret, pig and human epithelia also shared serotype-specific differences in the polarity (apical vs basolateral) and proteasome dependence of rAAV transduction. Despite these parallels, N-linked sialic acid receptors were required for rAAV1 and rAAV5 transduction of human and mouse airway epithelia, but not ferret or pig airway epithelia. Hence, although the airway tropisms of rAAV serotypes 1, 2 and 5 are conserved better among ferret, pig and human as compared to mouse, viral receptors/ co- receptors appear to maintain considerable species diversity.