Murine norovirus virulence factor 1 (VF1) protein contributes to viral fitness during persistent infection
Murine norovirus virulence factor 1 (VF1) protein contributes to viral fitness during persistent infection
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鼠诺如病毒毒力因子 1 (VF1) 蛋白有助于持续感染期间的病毒适应性
DOI：
10.1101/646281
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发表时间：
2019
期刊：
影响因子：
--
通讯作者：
Borg C
中科院分区：
文献类型：
--
作者：
Borg C
小鼠诺如病毒（MNV）被广泛用作研究诺如病毒生物学的模型。虽然MNV分离株的发病机制各不相同，但免疫能力强的小鼠感染大多导致持续感染。病毒建立持续性感染的能力取决于其破坏或避免宿主免疫反应的能力。先前，我们描述了MNV中毒力因子1 （VF1）的鉴定和表征，并证明了其作为先天免疫拮抗剂的作用。在这里，我们探讨了VF1在免疫功能正常的宿主持续MNV感染中的作用。利用反向遗传学，我们产生了携带插入VF1 ORF的单个或三个终止密码子的MNV-3病毒。vf1缺失的MNV-3在组织培养中复制到与野生型病毒相当的水平。MNV-3与MNV-1急性毒株的比较研究表明，MNV-3 VF1与MNV-1 VF1具有相同的功能，但效力有所降低。在感染的急性期，C57BL/6小鼠感染VF1缺失的MNV-3后，复制动力学显著降低，但在表型恢复VF1表达后，病毒载量迅速达到野生型病毒感染小鼠的水平。在VF1中插入三个终止密码子的MNV-3突变体感染后，其逆转被抑制，在小鼠持续感染3个月的过程中，导致复制持续降低，这表明VF1在体内病毒适应性中发挥了作用。我们的研究结果表明，由MNV持续菌株表达的VF1也具有拮抗感染的先天反应的功能。我们发现VF1对病毒的持久性并不是必需的，而是有助于病毒在小鼠中的适应性。这些数据符合诺如病毒利用多种机制来避免和/或控制宿主对感染的反应的假设，而VF1只是其中的一个组成部分。
Murine norovirus (MNV) is widely used as a model for studying norovirus biology. While MNV isolates vary in their pathogenesis, infection of immunocompetent mice mostly results in persistent infection. The ability of a virus to establish a persistent infection is dependent on its ability to subvert or avoid the host immune response. Previously, we described the identification and characterization of virulence factor 1 (VF1) in MNV, and demonstrated its role as an innate immune antagonist. Here, we explore the role of VF1 during persistent MNV infection in an immunocompetent host. Using reverse genetics, we generated MNV-3 viruses carrying a single or a triple termination codon inserted in the VF1 ORF. VF1-deleted MNV-3 replicated to comparable levels to the wildtype virus in tissue culture. Comparative studies between MNV-3 and an acute MNV-1 strain show that MNV-3 VF1 exerts the same functions as MNV-1 VF1, but with reduced potency. C57BL/6 mice infected with VF1-deleted MNV-3 showed significantly reduced replication kinetics during the acute phase of the infection, but viral loads rapidly reached the levels seen in mice infected with wildtype virus after phenotypic restoration of VF1 expression. Infection with an MNV-3 mutant that had three termination codons inserted into VF1, in which reversion was suppressed, resulted in consistently lower replication throughout a 3 month persistent infection in mice, suggesting a role for VF1 in viral fitnessin vivo. Our results indicate that VF1 expressed by a persistent strain of MNV also functions to antagonize the innate response to infection. We found that VF1 is not essential for viral persistence, but instead contributes to viral fitness in mice. These data fit with the hypothesis that noroviruses utilize multiple mechanisms to avoid and/or control the host response to infection and that VF1 is just one component of this.
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影响因子：
30.3
作者：
Lee S;Wilen CB;Orvedahl A;McCune BT;Kim KW;Orchard RC;Peterson ST;Nice TJ;Baldridge MT;Virgin HW
通讯作者：
Virgin HW
DOI：
10.1126/science.aar3799
发表时间：
2018-04-13
期刊：
Science (New York, N.Y.)
影响因子：
--
作者：
Wilen CB;Lee S;Hsieh LL;Orchard RC;Desai C;Hykes BL Jr;McAllaster MR;Balce DR;Feehley T;Brestoff JR;Hickey CA;Yokoyama CC;Wang YT;MacDuff DA;Kreamalmayer D;Howitt MR;Neil JA;Cadwell K;Allen PM;Handley SA;van Lookeren Campagne M;Baldridge MT;Virgin HW
通讯作者：
Virgin HW
影响因子：
15.9
作者：
Nice TJ;Robinson BA;Van Winkle JA
通讯作者：
Van Winkle JA
影响因子：
--
作者：
Thorne L;Lu J;Chaudhry Y;Goodfellow I
通讯作者：
Goodfellow I
野生啮齿动物种群中鼠诺如病毒的多样性：物种特异性关联表明存在古老的分歧。
DOI：
10.1099/vir.0.036392-0
发表时间：
2012
期刊：
The Journal of general virology
影响因子：
--
作者：
Donald B. Smith;Nora McFadden;R. Blundell;A. Meredith;P. Simmonds
通讯作者：
P. Simmonds