Laboratory of Persistent Viral Diseases, Rocky Mountain Laboratories, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Hamilton, Montana, USA.
Laboratory of Persistent Viral Diseases, Rocky Mountain Laboratories, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Hamilton, Montana, USA
J Virol. 2014 Oct;88(19):11070-9. doi: 10.1128/JVI.01866-14. Epub 2014 Jul 9.
La Crosse virus (LACV) is the major cause of pediatric viral encephalitis in the United States; however, the mechanisms responsible for age-related susceptibility in the pediatric population are not well understood. Our current studies in a mouse model of LACV infection indicated that differences in myeloid dendritic cell (mDC) responses between weanling and adult mice accounted for susceptibility to LACV-induced neurological disease. We found that type I interferon (IFN) responses were significantly stronger in adult than in weanling mice. Production of these IFNs required both endosomal Toll-like receptors (TLRs) and cytoplasmic RIG-I-like receptors (RLRs). Surprisingly, IFN expression was not dependent on plasmacytoid DCs (pDCs) but rather was dependent on mDCs, which were found in greater number and induced stronger IFN responses in adults than in weanlings. Inhibition of these IFN responses in adults resulted in susceptibility to LACV-induced neurological disease, whereas postinfection treatment with type I IFN provided protection in young mice. These studies provide a definitive mechanism for age-related susceptibility to LACV encephalitis, where mDCs in young mice are insufficiently activated to control peripheral virus replication, thereby allowing virus to persist and eventually cause central nervous system (CNS) disease.
La Crosse virus (LACV) is the primary cause of pediatric viral encephalitis in the United States. Although the virus infects both adults and children, over 80% of the reported neurological disease cases are in children. To understand why LACV causes neurological disease primarily in young animals, we used a mouse model where weanling mice, but not adult mice, develop neurological disease following virus infection. We found that an early immune response cell type, myeloid dendritic cells, was critical for protection in adult animals and that these cells were reduced in young animals. Activation of these cells during virus infection or after treatment with type I interferon in young animals provided protection from LACV. Thus, this study demonstrates a reason for susceptibility to LACV infection in young animals and shows that early therapeutic treatment in young animals can prevent neurological disease.
在美国，拉科萨病毒（LACV）是导致小儿病毒性脑炎的主要原因；然而，小儿人群中与年龄相关的易感性的机制尚不清楚。我们目前在 LACV 感染的小鼠模型中的研究表明，幼鼠和成年鼠之间髓样树突状细胞（mDC）反应的差异是导致 LACV 诱导的神经疾病易感性的原因。我们发现，成年鼠的 I 型干扰素（IFN）反应明显强于幼鼠。这些 IFN 的产生既需要内体 Toll 样受体（TLR），也需要细胞质 RIG-I 样受体（RLR）。令人惊讶的是，IFN 表达不依赖于浆细胞样 DC（pDC），而是依赖于 mDC，成年鼠中 mDC 的数量更多，诱导的 IFN 反应更强。成年鼠中这些 IFN 反应的抑制导致了对 LACV 诱导的神经疾病的易感性，而年轻小鼠感染后用 I 型 IFN 治疗可提供保护。这些研究为 LACV 脑炎的年龄相关易感性提供了明确的机制，即幼鼠中的 mDC 不足以激活以控制外周病毒复制，从而允许病毒持续存在并最终导致中枢神经系统（CNS）疾病。
拉科萨病毒（LACV）是美国小儿病毒性脑炎的主要原因。尽管该病毒感染成年人和儿童，但报告的神经疾病病例中超过 80%是儿童。为了了解为什么 LACV 主要导致年幼动物发生神经疾病，我们使用了一种小鼠模型，其中幼鼠而非成年鼠在病毒感染后会发展为神经疾病。我们发现，一种早期的免疫反应细胞类型，髓样树突状细胞，对成年动物的保护至关重要，而这些细胞在幼鼠中减少。在病毒感染期间或在年轻动物中用 I 型干扰素治疗后激活这些细胞可提供对 LACV 的保护。因此，这项研究表明了幼小动物对 LACV 感染的易感性的原因，并表明在幼小动物中早期治疗可以预防神经疾病。
