Castro-Jorge Luiza A, Pretto Carla D, Smith Asa B, Foreman Oded, Carnahan Kelly E, Spindler Katherine R
Department of Microbiology and Immunology, University of Michigan, Ann Arbor, Michigan, USA.
Department of Pathology, Genentech, Inc., South San Francisco, California, USA.
J Virol. 2017 Jan 31;91(4). doi: 10.1128/JVI.02106-16. Print 2017 Feb 15.
Interleukin-1β (IL-1β), an inflammatory cytokine and IL-1 receptor ligand, has diverse activities in the brain. We examined whether IL-1 signaling contributes to the encephalitis observed in mouse adenovirus type 1 (MAV-1) infection, using mice lacking the IL-1 receptor (Il1r1 mice). Il1r1 mice demonstrated reduced survival, greater disruption of the blood-brain barrier (BBB), higher brain viral loads, and higher brain inflammatory cytokine and chemokine levels than control C57BL/6J mice. We also examined infections of mice defective in IL-1β production (Pycard mice) and mice defective in trafficking of Toll-like receptors to the endosome (Unc93b1 mice). Pycard and Unc93b1 mice showed lower survival (similar to Il1r1 mice) than control mice but, unlike Il1r1 mice, did not have increased brain viral loads or BBB disruption. Based on the brain cytokine levels, MAV-1-infected Unc93b1 mice had a very different inflammatory profile from infected Il1r1 and Pycard mice. Histological examination demonstrated pathological findings consistent with encephalitis in control and knockout mice; however, intranuclear viral inclusions were seen only in Il1r1 mice. A time course of infection of control and Il1r1 mice evaluating the kinetics of viral replication and cytokine production revealed differences between the mouse strains primarily at 7 to 8 days after infection, when mice began succumbing to MAV-1 infection. In the absence of IL-1 signaling, we noted an increase in the transcription of type I interferon (IFN)-stimulated genes. Together, these results indicate that IL-1 signaling is important during MAV-1 infection and suggest that, in its absence, increased IFN-β signaling may result in increased neuroinflammation.
The investigation of encephalitis pathogenesis produced by different viruses is needed to characterize virus and host-specific factors that contribute to disease. MAV-1 produces viral encephalitis in its natural host, providing a good model for studying factors involved in encephalitis development. We investigated the role of IL-1 signaling during MAV-1-induced encephalitis. Unexpectedly, the lack of IL-1 signaling increased the mortality and inflammation in mice infected with MAV-1. Also, there was an increase in the transcription of type I IFN-stimulated genes that correlated with the observed increased mortality and inflammation. The findings highlight the complex nature of encephalitis and suggests that IL-1 has a protective effect for the development of MAV-1-induced encephalitis.
白细胞介素-1β（IL-1β）是一种炎症细胞因子和IL-1受体配体，在大脑中具有多种活性。我们使用缺乏IL-1受体的小鼠（Il1r1小鼠），研究了IL-1信号通路是否参与1型小鼠腺病毒（MAV-1）感染中观察到的脑炎。与对照C57BL/6J小鼠相比，Il1r1小鼠存活率降低，血脑屏障（BBB）破坏更严重，脑病毒载量更高，脑内炎症细胞因子和趋化因子水平更高。我们还检测了IL-1β产生缺陷的小鼠（Pycard小鼠）和Toll样受体向内体转运缺陷的小鼠（Unc93b1小鼠）的感染情况。Pycard和Unc93b1小鼠的存活率低于对照小鼠（与Il1r1小鼠相似），但与Il1r1小鼠不同的是，它们的脑病毒载量没有增加，BBB也没有破坏。根据脑内细胞因子水平，MAV-1感染的Unc93b1小鼠的炎症特征与感染的Il1r1和Pycard小鼠有很大不同。组织学检查显示对照小鼠和基因敲除小鼠均有与脑炎一致的病理表现；然而，仅在Il1r1小鼠中可见核内病毒包涵体。对对照小鼠和Il1r1小鼠感染过程的时间进程进行评估，以观察病毒复制和细胞因子产生的动力学，结果显示主要在感染后7至8天，小鼠开始死于MAV-1感染时，这两种小鼠品系之间存在差异。在缺乏IL-1信号的情况下，我们注意到I型干扰素（IFN）刺激基因的转录增加。总之，这些结果表明IL-1信号通路在MAV-1感染期间很重要，并提示在其缺失时，IFN-β信号通路增加可能导致神经炎症增加。
需要对不同病毒引起的脑炎发病机制进行研究，以确定导致疾病的病毒和宿主特异性因素。MAV-1在其自然宿主中引起病毒性脑炎，为研究脑炎发展相关因素提供了一个良好模型。我们研究了IL-1信号通路在MAV-1诱导的脑炎中的作用。出乎意料的是，缺乏IL-1信号通路会增加感染MAV-1小鼠的死亡率和炎症反应。此外，I型IFN刺激基因的转录增加，这与观察到的死亡率和炎症反应增加相关。这些发现突出了脑炎的复杂性，并提示IL-1对MAV-1诱导的脑炎发展具有保护作用。
