Heparin-binding and patterns of virulence for two recombinant strains of Sindbis virus
Heparin-binding and patterns of virulence for two recombinant strains of Sindbis virus
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DOI：
10.1016/j.virol.2005.11.034
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发表时间：
2006-03-30
期刊：
影响因子：
3.7
通讯作者：
Griffin, DE
中科院分区：
文献类型：
--
作者：
Bear, JS;Byrnes, AP;Griffin, DE
E2是辛德毕斯病毒神经毒力的重要决定因子。硫酸乙酰肝素（HS）结合增加与病毒血症的快速清除相关，通常与毒力降低相关。然而，在新生CD-1小鼠中，组氨酸取代E2 -157处的精氨酸（R157 H）或谷氨酸取代E2-159处的赖氨酸（K159 E）产生的病毒具有肝素-琼脂糖结合的降低和病毒血症的增加，但与HS表达细胞的结合水平和毒力表型不同（Byrnes，A. P.，格里芬，D.E.，2000.辛德比斯病毒的大斑块突变体显示出与硫酸乙酰肝素的结合减少、病毒血症加剧和从循环中清除的速度减慢。J. Virol. 74，644-651）。为了确定毒力机制，在新生CD-1和BALB/c小鼠中研究了R157 H和K159 E。皮下接种R157 H和K159 E的2日龄CD-1小鼠死亡率分别为100%和60%。在2日龄BALB/c小鼠中，R157 H引起25%的死亡，K159 E没有引起死亡。R157 H和K159 E在接种部位复制相似，具有相同水平的病毒血症，但CD-1小鼠的清除速度比BALB/c小鼠慢。皮下和脑内接种后，R157 H在中枢神经系统（CNS）和未分化神经元中的复制优于K159 E。这些研究表明，在新生BALB/c小鼠的复制的遗传限制，影响结合蛋白聚糖的氨基酸取代可能不同的重要性中枢神经系统感染和病毒血症。(C)2005年爱思唯尔公司All rights reserved.
E2 is an important determinant of Sindbis virus neurovirulence. Increased heparan Sulfate (HS) binding is associated with rapid clearance of viremia and Usually with decreased virulence. However, substitution of histidine for arginine at E2-157 (R157H) or glutamate for lysine at E2-159 (K159E) produces viruses with decreases in heparin-Sepharose binding and increases in viremia but different levels of binding to HS-expressing cells and virulence phenotypes in newborn CD-1 mice (Byrnes, A.P., Griffin, D.E., 2000. Large-plaque mutants of Sindbis virus show reduced binding to heparan sulfate, heightened viremia and slower clearance from the circulation. J. Virol. 74, 644-651). To identify mechanisms of virulence, R157H and K159E were studied in newborn CD-1 and BALB/c mice. Subcutaneous inoculation of R157H caused 100% and K159E 60% mortality in 2-day-old CD-1 mice. R157H caused 25% and K159E no mortality in 2-day-old BALB/c mice. R157H and K159E replicated similarly at the site of inoculation with the same level of viremia, but clearance was slower in CD-1 than BALB/c mice. R157H replicated better than K159E in the central nervous system (CNS) after subcutaneous and intracerebral inoculation and in undifferentiated neurons. These studies show a genetic restriction of replication in newborn BALB/c mice, and that amino acid substitutions affecting binding to proteoglycans may differ in importance for CNS infection and viremia. (C) 2005 Elsevier Inc. All rights reserved.