PDF(Pubmed)
Abstract：
RNA viruses adapt rapidly to new host environments by generating highly diverse genome sets, so-called \"quasispecies.\" Minor genetic variants promote their rapid adaptation, allowing for the emergence of drug-resistance or immune-escape mutants. Understanding these adaptation processes is highly relevant to assessing the risk of cross-species transmission and the safety and efficacy of vaccines and antivirals. We hypothesized that genetic memory within a viral genome population facilitates rapid adaptation. To test this, we investigated the adaptation of the Morbillivirus canine distemper virus to ferrets and compared an attenuated, Vero cell-adapted virus isolate with its recombinant derivative over consecutive ferret passages. Although both viruses adapted to the new host, the reduced initial genetic diversity of the recombinant virus resulted in delayed disease onset. The non-recombinant virus gradually increased the frequencies of beneficial mutations already present at very low frequencies in the input virus. In contrast, the recombinant virus first evolved de novo mutations to compensate for the initial fitness impairments. Importantly, while both viruses evolved different sets of mutations, most mutations found in the adapted non-recombinant virus were identical to those found in a previous ferret adaptation experiment with the same isolate, indicating that mutations present at low frequency in the original virus stock serve as genetic memory. An arginine residue at position 519 in the carboxy terminus of the nucleoprotein shared by all adapted viruses was found to contribute to pathogenesis in ferrets. Our work illustrates the importance of genetic diversity for adaptation to new environments and identifies regions with functional relevance.IMPORTANCEWhen viruses encounter a new host, they can rapidly adapt to this host and cause disease. How these adaptation processes occur remains understudied. Morbilliviruses have high clinical and veterinary relevance and are attractive model systems to study these adaptation processes. The canine distemper virus is of particular interest, as it exhibits a broader host range than other morbilliviruses and frequently crosses species barriers. Here, we compared the adaptation of an attenuated virus and its recombinant derivative to that of ferrets. Pre-existing mutations present at low frequency allowed faster adaptation of the non-recombinant virus compared to the recombinant virus. We identified a common point mutation in the nucleoprotein that affected the pathogenesis of both viruses. Our study shows that genetic memory facilitates environmental adaptation and that erasing this genetic memory by genetic engineering results in delayed and different adaptation to new environments, providing an important safety aspect for the generation of live-attenuated vaccines.
摘要：
RNA病毒通过产生高度多样化的基因组来快速适应新的宿主环境。所谓的“准物种”。“微小的遗传变异促进了它们的快速适应，允许耐药性或免疫逃逸突变体的出现。了解这些适应过程与评估跨物种传播的风险以及疫苗和抗病毒药物的安全性和有效性高度相关。我们假设病毒基因组群体内的遗传记忆有助于快速适应。为了测试这个，我们调查了麻疹病毒犬瘟热病毒对雪貂的适应性，经过连续雪貂传代的Vero细胞适应性病毒分离物及其重组衍生物。尽管两种病毒都适应了新的宿主，重组病毒的初始遗传多样性降低导致疾病发作延迟。非重组病毒逐渐增加了输入病毒中以非常低的频率已经存在的有益突变的频率。相比之下,重组病毒首先进化出从头突变来补偿最初的适应性损害。重要的是,虽然两种病毒进化出不同的突变，在适应的非重组病毒中发现的大多数突变与先前使用相同分离株的雪貂适应实验中发现的突变相同，表明原始病毒库存中存在的低频率突变可作为遗传记忆。发现所有适应的病毒共享的核蛋白羧基末端519位的精氨酸残基有助于雪貂的发病机理。我们的工作说明了遗传多样性对适应新环境的重要性，并确定了具有功能相关性的区域。重要信息当病毒遇到新的宿主时，它们可以迅速适应这种宿主并引起疾病。这些适应过程是如何发生的，仍未得到充分研究。麻疹病毒具有很高的临床和兽医相关性，并且是研究这些适应过程的有吸引力的模型系统。犬瘟热病毒是特别感兴趣的，因为它表现出比其他麻疹病毒更广泛的宿主范围，并且经常跨越物种障碍。这里,我们比较了减毒病毒及其重组衍生物与雪貂的适应性。与重组病毒相比,以低频率存在的预先存在的突变允许非重组病毒更快地适应。我们确定了影响两种病毒发病机理的核蛋白中的常见点突变。我们的研究表明，遗传记忆有助于环境适应，并且通过基因工程消除这种遗传记忆会导致对新环境的延迟和不同适应，为减毒活疫苗的生产提供了重要的安全性方面。
