Srinivas Mridula Annaswamy, Orchard Robert C
Department of Immunology, University of Texas Southwestern Medical Center, Dallas, TX, USA.
Department of Microbiology, University of Texas Southwestern Medical Center, Dallas, TX, USA.
bioRxiv. 2025 Aug 27:2025.08.27.672596. doi: 10.1101/2025.08.27.672596.
Viruses can rapidly adapt and evolve to new, unfavorable environments due to their decreased replication fidelity, large reproductive index, and short life cycle. Often these adaptations that enable increased fitness in a new, specialized environment comes with a trade-off of decreased fitness in a standard, general environment. Understanding the tradeoffs of generalist and specialist viruses has provided important insight into vaccine development, mechanism of action of antivirals, and function of viral proteins. Here, we sought to identify how a specialist murine norovirus (MNV) could be converted to a generalist without a simple reversion of a genetic mutation. Previously, we found that a mutation in MNV (NS6) overcame restriction by host protein Trim7 but decreased the efficiency of viral polyprotein NS6-7 cleavage and resulted in attenuation of this specialist virus. Here, we find that a single valine-to-isoleucine mutation in MNV non-structural protein NS4 (NS4) is sufficient to rescue the attenuated replication of specialist NS6 over multiple cycles of replication. However, NS4 did not affect the defective polyprotein cleavage but instead the NS4 mutation facilitates faster viral spread in vitro independent of interferon signaling. The emergence of this mutation in NS4 suggests an unappreciated connection between NS4 and NS6 during norovirus replication and provides a system to define the unknown role of norovirus NS4 during infection.
由于病毒复制保真度降低、繁殖指数高和生命周期短，它们能够迅速适应并进化到新的不利环境。通常，这些能在新的特殊环境中提高适应性的适应能力，是以在标准的一般环境中适应性降低为代价的。了解泛嗜性病毒和嗜性病毒的权衡，为疫苗开发、抗病毒药物的作用机制以及病毒蛋白的功能提供了重要见解。在这里，我们试图确定一种嗜性小鼠诺如病毒（MNV）如何在不简单地逆转基因突变的情况下转变为泛嗜性病毒。此前，我们发现MNV（NS6）中的一个突变克服了宿主蛋白Trim7的限制，但降低了病毒多聚蛋白NS6-7的切割效率，并导致这种嗜性病毒的减毒。在这里，我们发现MNV非结构蛋白NS4（NS4）中的单个缬氨酸到异亮氨酸突变足以在多个复制周期中挽救嗜性NS6的减毒复制。然而，NS4并不影响有缺陷的多聚蛋白切割，而是NS4突变促进了病毒在体外更快地传播，且不依赖于干扰素信号传导。NS4中这种突变的出现表明，在诺如病毒复制过程中，NS4和NS6之间存在一种未被认识到的联系，并提供了一个系统来定义诺如病毒NS4在感染过程中的未知作用。
