Limited trafficking of a neurotropic virus through inefficient retrograde axonal transport and the type I interferon response.
Limited trafficking of a neurotropic virus through inefficient retrograde axonal transport and the type I interferon response.
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DOI：
10.1371/journal.ppat.1000791
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发表时间：
2010-03-05
期刊：
影响因子：
6.7
通讯作者：
Pfeiffer JK
中科院分区：
文献类型：
--
作者：
Lancaster KZ;Pfeiffer JK
脊髓灰质炎病毒是一种肠道病毒，很少侵入人类中枢神经系统（CNS）。为了确定限制脊髓灰质炎病毒从外周向中枢神经系统传播的障碍，我们监测了10种标记病毒的贩运。经口接种易感小鼠后，脊髓灰质炎病毒存在于周围神经元，包括迷走神经和坐骨神经。为了模拟病毒在外周神经元中的运输，我们向小鼠肌肉注射脊髓灰质炎病毒，其遵循肌肉-坐骨神经-脊髓-脑途径。只有20%的脊髓灰质炎病毒群成功从肌肉转移到大脑，并发现了限制病毒贩运的三个障碍。首先，使用光敏病毒，我们发现在外周神经元中病毒复制有限。其次，脊髓灰质炎病毒在外周神经元中的逆行轴突运输效率低下;然而，肌肉损伤后效率增加，这也增加了非病毒神经示踪剂麦胚凝集素的运输效率。第三，使用易感的干扰素（IFN）α/β受体敲除小鼠，我们证明了IFN应答限制了病毒从外周到大脑的运动。令人惊讶的是，逆行轴突运输屏障的强度相当于IFN屏障。说明了由IFN反应和低效轴突运输产生的屏障的重要性，肌肉损伤的IFN α/β受体敲除小鼠允许80%的病毒群体进入大脑，并且比屏障完整的小鼠快三倍死于疾病。这些结果表明，多个单独的障碍限制脊髓灰质炎病毒从外周神经元到中枢神经系统的运输，可能解释了罕见的麻痹性脊髓灰质炎的发病率。这项研究确定了低效的轴突运输作为脊髓灰质炎病毒在外周神经元中运输的实质性障碍，这可能限制其他病毒进入CNS。嗜神经病毒，包括疱疹病毒、狂犬病病毒和脊髓灰质炎病毒，在外周中启动感染，并且可以通过外周神经元移动到达中枢神经系统（CNS）。由于外周神经元可以长达一米，低效的神经运输可能会显着影响嗜神经病毒的发病机制。在这项研究中，我们使用了一种新的病毒“条形码”检测，以量化脊髓灰质炎病毒从外周运输到中枢神经系统的效率，使用小鼠模型。只有20%的脊髓灰质炎病毒群成功地从外周转移到中枢神经系统。我们发现脊髓灰质炎病毒在外周神经元中的转运效率非常低，先天免疫反应也限制了病毒的移动。令人惊讶的是，神经转运屏障与先天免疫反应屏障一样强大。重要的是，通过克服神经转运和先天免疫屏障，80%的脊髓灰质炎病毒群体成功地从外周转移到中枢神经系统，小鼠死于疾病的速度比屏障完整的小鼠快三倍。这项研究确定了低效的神经运输作为病毒在外周神经元中移动的实质性障碍，这可能限制许多病毒进入CNS。
Poliovirus is an enteric virus that rarely invades the human central nervous system (CNS). To identify barriers limiting poliovirus spread from the periphery to CNS, we monitored trafficking of 10 marked viruses. After oral inoculation of susceptible mice, poliovirus was present in peripheral neurons, including vagus and sciatic nerves. To model viral trafficking in peripheral neurons, we intramuscularly injected mice with poliovirus, which follows a muscle–sciatic nerve–spinal cord–brain route. Only 20% of the poliovirus population successfully moved from muscle to brain, and three barriers limiting viral trafficking were identified. First, using light-sensitive viruses, we found limited viral replication in peripheral neurons. Second, retrograde axonal transport of poliovirus in peripheral neurons was inefficient; however, the efficiency was increased upon muscle damage, which also increased the transport efficiency of a non-viral neural tracer, wheat germ agglutinin. Third, using susceptible interferon (IFN) α/β receptor knockout mice, we demonstrated that the IFN response limited viral movement from the periphery to the brain. Surprisingly, the retrograde axonal transport barrier was equivalent in strength to the IFN barrier. Illustrating the importance of barriers created by the IFN response and inefficient axonal transport, IFN α/β receptor knockout mice with muscle damage permitted 80% of the viral population to access the brain, and succumbed to disease three times faster than mice with intact barriers. These results suggest that multiple separate barriers limit poliovirus trafficking from peripheral neurons to the CNS, possibly explaining the rare incidence of paralytic poliomyelitis. This study identifies inefficient axonal transport as a substantial barrier to poliovirus trafficking in peripheral neurons, which may limit CNS access for other viruses. Neurotropic viruses, including herpesviruses, rabies virus, and poliovirus, initiate infection in the periphery and can move through peripheral neurons to reach the central nervous system (CNS). Since peripheral neurons can be up to one meter long, inefficient neural transport could dramatically affect pathogenesis of neurotropic viruses. In this study, we used a novel viral “bar-coding” assay to quantify the efficiency of poliovirus transport from the periphery to the CNS using a mouse model. Only 20% of the poliovirus population successfully moved from the periphery to the CNS. We discovered that transport of poliovirus in peripheral neurons was very inefficient, and the innate immune response also limited viral movement. Surprisingly, the neural transport barrier was as strong as the innate immune response barrier. Importantly, by overcoming both the neural transport and innate immune barriers, 80% of the poliovirus population successfully moved from the periphery to the CNS, and mice succumbed to disease three times faster than mice with intact barriers. This study identifies inefficient neural transport as a substantial barrier to viral movement in peripheral neurons, which may limit CNS access for many viruses.
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影响因子：
5.4
作者：
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影响因子：
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