Department of Neurosurgery, Yale University School of Medicine, New Haven, Connecticut, USA.
J Virol. 2014 Apr;88(7):3695-704. doi: 10.1128/JVI.03509-13. Epub 2014 Jan 15.
Serious permanent neurological or psychiatric dysfunction may result from virus infections in the central nervous system (CNS). Olfactory sensory neurons are in direct contact with the external environment, making them susceptible to infection by viruses that can enter the brain via the olfactory nerve. The rarity of full brain viral infections raises the important question of whether unique immune defense mechanisms protect the brain. Here we show that both RNA (vesicular stomatitis virus [VSV]) and DNA (cytomegalovirus [CMV]) virus inoculations of the nasal mucosa leading to olfactory bulb (OB) infection activate long-distance signaling that upregulates antiviral interferon (IFN)-stimulated gene (ISG) expression in uninfected remote regions of the brain. This signaling mechanism is dependent on IFN-α/β receptors deep within the brain, leading to the activation of a distant antiviral state that prevents infection of the caudal brain. In normal mice, VSV replication is limited to the OB, and these animals typically survive the infection. In contrast, mice lacking the IFN-α/β receptor succumbed to the infection, with VSV spreading throughout the brain. Chemical destruction of the olfactory sensory neurons blocked both virus trafficking into the OB and the IFN response in the caudal brain, indicating a direct signaling within the brain after intranasal infection. Most signaling within the brain occurs across the 20-nm synaptic cleft. The unique long-distance IFN signaling described here occurs across many millimeters within the brain and is critical for survival and normal brain function.
The olfactory mucosa can serve as a conduit for a number of viruses to enter the brain. Yet infections in the CNS rarely occur. The mechanism responsible for protecting the brain from viruses that successfully invade the OB, the first site of infection subsequent to infection of the nasal mucosa, remains elusive. Here we demonstrate that the protection is mediated by a long-distance interferon signaling, particularly IFN-β released by infected neurons in the OB. Strikingly, in the absence of neurotropic virus infection, ISGs are induced in the posterior regions of the brain, activating an antiviral state and preventing further virus invasion.
中枢神经系统 (CNS) 中的病毒感染可能导致严重的永久性神经或精神功能障碍。嗅觉感觉神经元直接与外部环境接触，使它们容易受到可通过嗅神经进入大脑的病毒的感染。完全脑部病毒感染的罕见性提出了一个重要问题，即是否存在独特的免疫防御机制来保护大脑。在这里，我们表明，鼻腔黏膜接种 RNA（水疱性口炎病毒 [VSV]）和 DNA（巨细胞病毒 [CMV]）病毒导致嗅球（OB）感染，会激活长距离信号，从而上调未感染的大脑远端区域的抗病毒干扰素（IFN）-刺激基因（ISG）表达。这种信号机制依赖于大脑深处的 IFN-α/β 受体，导致激活远处的抗病毒状态，从而防止尾端大脑感染。在正常小鼠中，VSV 复制仅限于 OB，并且这些动物通常能在感染中存活下来。相比之下，缺乏 IFN-α/β 受体的小鼠则因感染而死亡，VSV 会扩散到整个大脑。嗅觉感觉神经元的化学破坏阻断了病毒向 OB 的运输和尾部大脑的 IFN 反应，表明鼻腔内感染后大脑内存在直接信号。大脑内的大多数信号传递都发生在 20nm 的突触间隙内。此处描述的独特长距离 IFN 信号传递发生在大脑内的多个毫米范围内，对生存和正常大脑功能至关重要。
嗅觉黏膜可作为多种病毒进入大脑的通道。然而，中枢神经系统感染很少发生。负责保护大脑免受成功入侵 OB（鼻腔黏膜感染后继发的第一个感染部位）的病毒的机制仍不清楚。在这里，我们证明这种保护是由长距离干扰素信号介导的，特别是 OB 中感染神经元释放的 IFN-β。引人注目的是，在没有神经嗜性病毒感染的情况下，ISGs 会在大脑的后区诱导，激活抗病毒状态并防止进一步的病毒入侵。
