Schäfer Alexandra, Whitmore Alan C, Konopka Jennifer L, Johnston Robert E
Department of Microbiology and Immunology, Carolina Vaccine Institute, The University of North Carolina at Chapel Hill, Chapel Hill, North Carolina 27599, USA.
J Virol. 2009 May;83(9):4275-86. doi: 10.1128/JVI.02383-08. Epub 2009 Feb 18.
Venezuelan equine encephalitis virus (VEE) replicon particles (VRP) were used to model the initial phase of VEE-induced encephalitis in the mouse brain. VRP can target and infect cells as VEE, but VRP do not propagate beyond the first infected cell due to the absence of the structural genes. Direct intracranial inoculation of VRP into mice induced acute encephalitis with signs similar to the neuronal phase of wild-type VEE infection and other models of virus-induced encephalitis. Using the previously established VRP-mRNP tagging system, a new method to distinguish the host responses in infected cells from those in uninfected bystander cell populations, we detected a robust and rapid innate immune response in the central nervous system (CNS) by infected neurons and uninfected bystander cells. Moreover, this innate immune response in the CNS compromised blood-brain barrier integrity, created an inflammatory response, and directed an adaptive immune response characterized by proliferation and activation of microglia cells and infiltration of inflammatory monocytes, in addition to CD4(+) and CD8(+) T lymphocytes. Taken together, these data suggest that a naïve CNS has an intrinsic potential to induce an innate immune response that could be crucial to the outcome of the infection by determining the composition and dynamics of the adaptive immune response. Furthermore, these results establish a model for neurotropic virus infection to identify host and viral factors that contribute to invasion of the brain, the mechanism(s) whereby the adaptive immune response can clear the infection, and the role of the host innate response in these processes.
委内瑞拉马脑炎病毒（VEE）复制子颗粒（VRP）被用于模拟小鼠脑中VEE诱导的脑炎的初始阶段。VRP可以像VEE一样靶向并感染细胞，但由于缺乏结构基因，VRP不会在第一个被感染的细胞之外进行传播。将VRP直接颅内接种到小鼠中可诱发急性脑炎，其症状与野生型VEE感染的神经元阶段以及其他病毒诱导的脑炎模型相似。利用先前建立的VRP-mRNP标记系统，这是一种区分受感染细胞与未受感染旁观者细胞群体中宿主反应的新方法，我们检测到受感染的神经元和未受感染的旁观者细胞在中枢神经系统（CNS）中引发了强大而快速的先天免疫反应。此外，CNS中的这种先天免疫反应损害了血脑屏障的完整性，引发了炎症反应，并引导了一种适应性免疫反应，其特征除了CD4(+)和CD8(+) T淋巴细胞外，还有小胶质细胞的增殖和激活以及炎性单核细胞的浸润。综上所述，这些数据表明，未接触过病原体的CNS具有诱导先天免疫反应的内在潜力，这对于感染结果可能至关重要，因为它决定了适应性免疫反应的组成和动态。此外，这些结果建立了一种嗜神经性病毒感染模型，以识别有助于脑部侵袭的宿主和病毒因素、适应性免疫反应清除感染的机制以及宿主先天反应在这些过程中的作用。
