CCR5 limits cortical viral loads during West Nile virus infection of the central nervous system.
CCR5 limits cortical viral loads during West Nile virus infection of the central nervous system.
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DOI：
10.1186/s12974-015-0447-9
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发表时间：
2015-12-15
影响因子：
9.3
通讯作者：
Klein RS
中科院分区：
文献类型：
--
作者：
Durrant DM;Daniels BP;Pasieka T;Dorsey D;Klein RS
细胞介导的免疫对于清除脑炎黄病毒、西尼罗河病毒（WNV）引起的中枢神经系统（CNS）感染至关重要。我们实验室先前的研究表明，WNV感染的神经元表达化学引诱物，介导抗病毒白细胞进入CNS的招募。尽管趋化因子受体CCR 5已被证明在WNV感染期间在CNS宿主防御中发挥重要作用，但其在感染脑内的活性的区域效应尚未确定。我们使用CCR 5缺陷小鼠和建立的小鼠模型WNV脑炎，以确定CCR 5活性是否影响WNV水平在中枢神经系统内的区域特异性的方式。采用单因素或双因素方差分析进行组间统计学比较;随后采用Bonferroni事后检验比较个体平均值。通过对数秩检验分析存活率。使用Prism软件（GraphPad Prism）进行分析。所有数据均表示为平均值± SEM。如果P ≤ 0.05，则认为差异具有显著性。如前所述，CCR 5活性的缺乏导致皮下感染WNV后小鼠的症状性疾病和死亡率增加。对来自WNV感染的野生型和CCR 5 −/−小鼠的足垫、引流淋巴结、脾脏、嗅球和小脑中的病毒负荷的评估显示，基因型之间没有差异。相比之下，WNV感染的CCR 5 −/−小鼠在感染后第8天表现出皮质组织（包括海马）中病毒负荷显著增加。通过Luminex分析的CNS区域趋化因子表达研究显示，与类似感染的WT动物相比，WNV感染的CCR 5 −/−小鼠皮质中的CCR 5配体CCL 4和CCL 5的表达显著增加。然而，在WNV感染的CCR 5 −/−小鼠中，病毒载量和CCR 5配体的皮质升高与浸润单核细胞数量减少和血脑屏障通透性增加有关。这些数据表明，在响应于CNS的WNV感染时，趋化因子表达发生区域差异，并且皮质神经元需要CCR 5活性来限制该脑区域中的病毒负荷。
Cell-mediated immunity is critical for clearance of central nervous system (CNS) infection with the encephalitic flavivirus, West Nile virus (WNV). Prior studies from our laboratory have shown that WNV-infected neurons express chemoattractants that mediate recruitment of antiviral leukocytes into the CNS. Although the chemokine receptor, CCR5, has been shown to play an important role in CNS host defense during WNV infection, regional effects of its activity within the infected brain have not been defined. We used CCR5-deficient mice and an established murine model of WNV encephalitis to determine whether CCR5 activity impacts on WNV levels within the CNS in a region-specific fashion. Statistical comparisons between groups were made with one- or two-way analysis of variance; Bonferroni’s post hoc test was subsequently used to compare individual means. Survival was analyzed by the log-rank test. Analyses were conducted using Prism software (GraphPad Prism). All data were expressed as means ± SEM. Differences were considered significant if P ≤ 0.05. As previously shown, lack of CCR5 activity led to increased symptomatic disease and mortality in mice after subcutaneous infection with WNV. Evaluation of viral burden in the footpad, draining lymph nodes, spleen, olfactory bulb, and cerebellum derived from WNV-infected wild-type, and CCR5−/− mice showed no differences between the genotypes. In contrast, WNV-infected, CCR5−/− mice exhibited significantly increased viral burden in cortical tissues, including the hippocampus, at day 8 post-infection. CNS regional studies of chemokine expression via luminex analysis revealed significantly increased expression of CCR5 ligands, CCL4 and CCL5, within the cortices of WNV-infected, CCR5−/− mice compared with those of similarly infected WT animals. Cortical elevations in viral loads and CCR5 ligands in WNV-infected, CCR5−/− mice, however, were associated with decreased numbers of infiltrating mononuclear cells and increased permeability of the blood-brain barrier. These data indicate that regional differences in chemokine expression occur in response to WNV infection of the CNS, and that cortical neurons require CCR5 activity to limit viral burden in this brain region.