A point mutation in a herpesvirus polymerase determines neuropathogenicity
A point mutation in a herpesvirus polymerase determines neuropathogenicity
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DOI：
10.1371/journal.ppat.0030160
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发表时间：
2007-11-01
期刊：
影响因子：
6.7
通讯作者：
Davis-Poynter, Nicholas
中科院分区：
文献类型：
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作者：
Goodman, Laura B.;Loregian, Arianna;Davis-Poynter, Nicholas
马匹感染1型疱疹病毒(EHV-1)会导致呼吸道疾病、流产和神经系统疾病。分子流行病学研究表明，导致EHV-1 DNA聚合酶(N752/D752)氨基酸变异的单核苷酸多态与自然发生的毒株的神经致病潜力显著相关。为了验证这种单一氨基酸交换本身影响神经致病性的假设，我们产生了具有不同聚合酶序列的重组病毒。在这里，我们表明，N752突变病毒在自然宿主中没有引起神经系统症状，而D752病毒能够引起中枢神经系统炎症和共济失调。D752病毒引起的神经系统疾病伴随着病毒血症水平的显著增加(p=0.01)，但N752和D752病毒从鼻黏膜脱落的病毒数量相似。这两种病毒在成纤维细胞和上皮细胞中的复制动力学相似，但表现出不同的白细胞趋向性。最后，我们观察到N752突变体对针对病毒聚合酶的药物aphidiclin的敏感性显著增加(p<；0.001)。我们的结果表明，疱疹病毒酶中的单个氨基酸变异可以影响神经致病潜力，而不会对受感染动物的病毒脱落产生重大影响，这对种群中的水平传播非常重要。从进化的角度来看，这一观察结果非常有趣，并与表明N752DNA pol型在EHV-1人群中占主导地位的数据一致，这表明病毒在自然宿主中致病性的降低可能不会以降低个体间传播的效率为代价。
Infection with equid herpesvirus type 1 (EHV-1) leads to respiratory disease, abortion, and neurologic disorders in horses. Molecular epidemiology studies have demonstrated that a single nucleotide polymorphism resulting in an amino acid variation of the EHV-1 DNA polymerase (N752/D752) is significantly associated with the neuropathogenic potential of naturally occurring strains. To test the hypothesis that this single amino acid exchange by itself influences neuropathogenicity, we generated recombinant viruses with differing polymerase sequences. Here we show that the N752 mutant virus caused no neurologic signs in the natural host, while the D752 virus was able to cause inflammation of the central nervous system and ataxia. Neurologic disease induced by the D752 virus was concomitant with significantly increased levels of viremia (p=0.01), but the magnitude of virus shedding from the nasal mucosa was similar between the N752 and D752 viruses. Both viruses replicated with similar kinetics in fibroblasts and epithelial cells, but exhibited differences in leukocyte tropism. Last, we observed a significant increase(p < 0.001) in sensitivity of the N752 mutant to aphidicolin, a drug targeting the viral polymerase. Our results demonstrate that a single amino acid variation in a herpesvirus enzyme can influence neuropathogenic potential without having a major effect on virus shedding from infected animals, which is important for horizontal spread in a population. This observation is very interesting from an evolutionary standpoint and is consistent with data indicating that the N752 DNA pol genotype is predominant in the EHV-1 population, suggesting that decreased viral pathogenicity in the natural host might not be at the expense of less efficient inter-individual transmission.