Regulation of Norovirus Virulence by the VP1 Protruding Domain Correlates with B Cell Infection Efficiency.
Regulation of Norovirus Virulence by the VP1 Protruding Domain Correlates with B Cell Infection Efficiency.
复制标题
VP1 突出结构域对诺如病毒毒力的调节与 B 细胞感染效率相关。
DOI：
10.1128/jvi.02880-15
复制
发表时间：
2015
影响因子：
5.4
通讯作者：
Karst,StephanieM
中科院分区：
文献类型：
--
作者：
Zhu,Shu;Watanabe,Makiko;Kirkpatrick,Ericka;Murray,AkilahB;Sok,Ryneth;Karst,StephanieM
人诺如病毒是地球仪胃肠炎的主要病因，但引起疾病的致病机制尚未完全确定。鼠诺如病毒模型系统的可用性提供了阐明天然宿主中病毒和宿主毒力决定因素的机会。例如，先前的研究已经揭示了鼠诺如病毒衣壳蛋白VP1的突出结构域，特别是VP1的残基296，调节毒性感染。我们确定了一组非同义突变的开放阅读框2（ORF2）基因编码的VP1出现在持续感染的小鼠，并测试这些突变是否赋予病毒复制和毒力的表型变化。与以前的研究一致，我们证明了在位置296处的谷氨酸导致衰减。对于第一次，我们还证明，赖氨酸在这个位置是足以赋予毒力，否则减毒鼠诺如病毒株。此外，我们的研究揭示了病毒在B细胞中复制的效率与毒力之间的直接相关性。这些数据特别引人注目，因为导致B细胞复制减少和减毒的突变对病毒在巨噬细胞中复制的能力影响极小。因此，诺如病毒感染B细胞可能直接导致疾病的结果。重要人类诺如病毒是一个主要的全球性疾病的原因，但我们对他们的致病机制知之甚少。鼠诺如病毒模型系统的可用性有利于研究天然宿主生物体中的诺如病毒，并鉴定病毒和宿主致病决定因素。我们已经确定了一组突变出现在病毒衣壳蛋白VP1在小鼠持续感染。我们的数据表明，VP1的突出结构域调节病毒在B细胞中复制的能力，这与毒力直接相关。重要的是，削弱B细胞感染的突变对巨噬细胞感染的影响最小，揭示了B细胞感染在诺如病毒发病机制中的潜在关键作用。
Human noroviruses are a leading cause of gastroenteritis across the globe, but the pathogenic mechanisms responsible for disease are not well established. The availability of a murine norovirus model system provides the opportunity to elucidate viral and host determinants of virulence in a natural host. For example, previous studies have revealed that the protruding domain of the murine norovirus capsid protein VP1, specifically residue 296 of VP1, regulates virulent infection. We identified a panel of nonsynonymous mutations in the open reading frame 2 (ORF2) gene encoding VP1 that arose in persistently infected mice and tested whether these mutations conferred phenotypic changes to viral replication and virulence. Consistent with previous studies, we demonstrate that a glutamic acid at position 296 results in attenuation. For the first time, we also demonstrate that a lysine at this position is sufficient to confer virulence on an otherwise attenuated murine norovirus strain. Moreover, our studies reveal a direct correlation between the efficiency of viral replication in B cells and virulence. These data are especially striking because mutations causing reduced B cell replication and attenuation had minimal effects on the ability of the virus to replicate in macrophages. Thus, norovirus infection of B cells may directly contribute to disease outcome.IMPORTANCEHuman noroviruses are a major global cause of disease, yet we know very little about their pathogenic mechanisms. The availability of a murine norovirus model system facilitates investigation of noroviruses in a natural host organism and the identification of viral and host determinants of pathogenesis. We have identified a panel of mutations arising in the viral capsid protein VP1 during persistent infection of mice. Our data reveal that the protruding domain of VP1 regulates the ability of the virus to replicate in B cells, and this directly correlates with virulence. Importantly, mutations impairing B cell infection had minimal effects on macrophage infection, revealing a potentially critical role for B cell infection in norovirus pathogenesis.