Neural-Cell-Intrinsic NF-κB Signaling Enhances Reovirus Virulence.
Neural-Cell-Intrinsic NF-κB Signaling Enhances Reovirus Virulence.
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神经细胞内在 NF-κB 信号传导增强呼肠孤病毒毒力。
DOI：
10.1128/jvi.01442-22
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发表时间：
2023
影响因子：
5.4
通讯作者：
Dermody,TerenceS
中科院分区：
文献类型：
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作者：
Taylor,GwenM;Pruijssers,AndreaJ;Brigleb,PamelaH;Fiske,KayL;Shang,Pengcheng;Urbanek,Kelly;Brown,JudyJ;Rajasundaram,Dhivyaa;Dermody,TerenceS
与中枢神经系统病毒感染相关的细胞凋亡病理效应是发病率和死亡率的重要原因。呼肠孤病毒是一种嗜神经病毒，可引起神经元细胞凋亡，导致新生小鼠致死性脑炎。呼肠孤病毒引起的脑炎在种系NF-κB亚单位p50的消融中减少。目前尚不清楚NF-κB的促凋亡功能是由神经细胞内在过程介导的，还是NF-κB调节炎症细胞产生的细胞因子，还是两者兼有。为了确定细胞类型特异性NF-κB信号在呼肠孤病毒诱导的神经元损伤中的作用，我们使用theCre/loxPrecombination系统建立了神经细胞中缺乏NF-κB p65表达的小鼠。在颅内接种呼肠孤病毒后，50%的野生型（WT）小鼠死于感染，而90%以上缺乏神经细胞NF-κB p65 （Nsp65−/−）的小鼠存活。虽然WT和Nsp65 - / -小鼠大脑中的病毒载量相当，但组织学分析显示，与Nsp65 - / -小鼠相比，WT小鼠大脑中呼肠孤病毒抗原阳性区域对裂解caspase-3（细胞凋亡标志物）的免疫反应性增加。这些数据表明，神经内源性NF-κ b依赖因子是呼肠孤病毒神经毒力的重要介质。对呼肠孤病毒感染的WT和Nsp65 - / -小鼠大脑皮层的RNA测序分析表明，呼肠孤病毒感染后，神经元细胞中NF-κB的激活上调了与先天免疫、炎症和细胞死亡相关的基因。更好地了解细胞类型特异性NF-κ b依赖性信号在病毒神经发病机制中的作用，可以为开发针对和保护高度易感细胞群的新疗法提供信息。病毒性脑炎是全世界儿童和成人患病和死亡的原因之一，治疗选择有限。确定嗜神经病毒上调的共同宿主因子可以增强对病毒诱导的神经发病机制的理解，并有助于治疗方法的开发。尽管许多嗜神经病毒在感染过程中激活NF-κB，但NF-κB调控病毒神经发病机制并导致病毒性脑炎的机制尚不清楚。我们建立了神经组织中NF-κB表达减少的小鼠，研究NF-κB在呼肠孤病毒神经毒力中的作用，并在中枢神经系统中鉴定被NF-κB激活的基因对呼肠孤病毒感染的反应。缺乏神经细胞NF-κB的小鼠呼肠孤病毒感染后脑炎受到抑制。呼肠孤病毒在大脑中诱导了依赖于NF-κB信号的趋化因子谱，与其他嗜神经病毒诱导的趋化因子谱相似。这些数据提示了嗜神经病毒引起的脑炎的共同潜在机制和潜在的共同治疗靶点。
Pathological effects of apoptosis associated with viral infections of the central nervous system are an important cause of morbidity and mortality. Reovirus is a neurotropic virus that causes apoptosis in neurons, leading to lethal encephalitis in newborn mice. Reovirus-induced encephalitis is diminished in mice with germ line ablation of NF-κB subunit p50. It is not known whether the proapoptotic function of NF-κB is mediated by neural-cell-intrinsic (neural-intrinsic) processes, NF-κB-regulated cytokine production by inflammatory cells, or a combination of both. To determine the contribution of cell type-specific NF-κB signaling in reovirus-induced neuronal injury, we established mice that lack NF-κB p65 expression in neural cells using theCre/loxPrecombination system. Following intracranial inoculation of reovirus, 50% of wild-type (WT) mice succumbed to infection, whereas more than 90% of mice lacking neural cell NF-κB p65 (Nsp65−/−) survived. While viral loads in brains of WT and Nsp65−/−mice were comparable, histological analysis revealed that reovirus antigen-positive areas in the brains of WT mice displayed increased immunoreactivity for cleaved caspase-3, a marker of apoptosis, relative to Nsp65−/−mice. These data suggest that neural-intrinsic NF-κB-dependent factors are essential mediators of reovirus neurovirulence. RNA sequencing analysis of reovirus-infected brain cortices of WT and Nsp65−/−mice suggests that NF-κB activation in neuronal cells upregulates genes involved in innate immunity, inflammation, and cell death following reovirus infection. A better understanding of the contribution of cell type-specific NF-κB-dependent signaling to viral neuropathogenesis could inform development of new therapeutics that target and protect highly vulnerable cell populations.IMPORTANCEViral encephalitis contributes to illness and death in children and adults worldwide and has limited treatment options. Identifying common host factors upregulated by neurotropic viruses can enhance an understanding of virus-induced neuropathogenesis and aid in development of therapeutics. Although many neurotropic viruses activate NF-κB during infection, mechanisms by which NF-κB regulates viral neuropathogenesis and contributes to viral encephalitis are not well understood. We established mice in which NF-κB expression is ablated in neural tissue to study the function of NF-κB in reovirus neurovirulence and identify genes activated by NF-κB in response to reovirus infection in the central nervous system. Encephalitis following reovirus infection was dampened in mice lacking neural cell NF-κB. Reovirus induced a chemokine profile in the brain that was dependent on NF-κB signaling and was similar to chemokine profiles elicited by other neurotropic viruses. These data suggest common underlying mechanisms of encephalitis caused by neurotropic viruses and potentially shared therapeutic targets.