VIRAL-INFECTION AND HOST DEFENSE
VIRAL-INFECTION AND HOST DEFENSE
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DOI：
10.1126/science.186.4170.1172
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发表时间：
1974-01-01
期刊：
影响因子：
56.9
通讯作者：
DECLERCQ, E
中科院分区：
文献类型：
--
作者：
CARTER, WA;DECLERCQ, E
双链RNA作为大多数（如果不是全部的话）病毒复制的中间物质，在病毒感染的发病机制和恢复过程中可能发挥比迄今所怀疑的更重要的作用。显然，双链RNA被攻击病毒和宿主细胞都用来试图获得“分子控制”。“双链RNA发挥一系列作用，这些作用不仅在单个细胞的水平上，而且在称为生物体的这些细胞的复杂组合中可能得到很好的平衡（图1）。在细胞中，干扰素的合成被触发，尽管如果dsRNA过快地关闭蛋白质合成，干扰素mRNA的翻译可能不会发生。在整个生物体中，疾病的严重程度将取决于感染引起的某些毒性反应（如细胞坏死和发烧）被宿主防御机制的增加所抵消（例如，免疫应答和干扰素产生）。应答的许多方面，涉及疾病的进展或从疾病中恢复，除了引起对dsRNA的生物动力学作用的注意之外，我们的假设还提出了特定的实验载体，这些载体被设计成增强我们关于病毒感染所发生的病态过程的分子基础的信息。最后，我们认为，虽然dsRNA分子可以被看作是一个相当简单的单元结构，一个给定的dsRNA分子的生物活性的进一步多样性的机会总是存在的。也就是说，每一次偏离完美的双螺旋排列都有可能以牺牲另一种生物反应性为代价来强调一种生物反应性。后一种结构-活性特性可能部分解释了在病毒学疾病表现中常见的极端明显多样性。在提交本文之后，我们发现dsRNA对淋巴细胞（鼠和人）的有效促有丝分裂作用也对输入聚合物对的碱基配对的保真度非常敏感（59）。例如，在一个完全螺旋的rIn rCn分子[例如，rIn r（C19，U）n]中，不常见的“环”（每20个碱基对一个核苷酸）强烈地改变了它的促有丝分裂特性。这一观察结果支持了我们的论点，即可以为生物系统中由dsRNA触发的其他反应开发一个“精细结构”术语，强调了表面上均匀的dsRNA家族可能会遇到不同的生物效应。
Double-stranded RNA, made as an intermediary substance in the replication of most, if not all, viruses, may play a much more important role in the pathogenesis and the recovery from virus infections than has hitherto been suspected. Apparently, dsRNA is used by both the challenge virus and the host cell in an attempt to gain "molecular control." Double-stranded RNA exerts a set of effects, which may be well balanced, not only at the level of the individual cell but also at the complex assemblage of these cells termed the organism (Fig. 1). In the cell, interferon synthesis is triggered, although interferon mRNA translation may not occur if dsRNA shuts off protein synthesis too quickly. In the whole organism, the disease severity will depend on how certain toxic reactions evoked by infection (such as cell necrosis and fever) are counterbalanced by an increase in the host defense mechanisms (for example, immune responsiveness and interferon production).Many aspects of the response, relating to either progress of, or recovery from, the disease, can be explained on the basis of a dsRNA.In addition to drawing attention to the biodynamic role of dsRNA, our hypothesis suggests specific experimental vectors designed to enhance our information on the molecular basis of the morbid process which occurs with viral infection. Finally, we suggest that, although the dsRNA molecule may be viewed as a rather simple unit structure, the opportunity for further diversity in the biological activity of a given dsRNA molecule always exists. Namely, each deviation from a perfectly double-helical arrangement introduces the possibility for emphasizing one biological reactivity at the expense of another. This latter structure-activity property may partially account for the extreme apparent diversity, commonly encountered, in the presentations of virologic illness.Appendix note added in proof. Subsequent to submission of this text, we have found that the potent mitogen effect of dsRNA for lymphocytes (murine and human) is also exquisitively sensitive to the fidelity in base pairing of the input polymer pair (59). For example, infrequent "loops" (one nucleotide per 20 base pairs) in an otherwise perfectly helical rIn⋅ rCnmolecule [for example, rIn⋅ r(C19,U)n] strongly changes its mitogenic properties. This observation, which supports our thesis that a "fine structure" term can be developed for other reactions triggered by dsRNA's in biological systems, emphasizes that diverse biological effects may be encountered with an ostensibly uniform family of dsRNA's.