Regulation of Lentivirus Neurovirulence by Lipopolysaccharide Conditioning: Suppression of CXCL10 in the Brain by IL-10
Regulation of Lentivirus Neurovirulence by Lipopolysaccharide Conditioning: Suppression of CXCL10 in the Brain by IL-10
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DOI：
10.4049/jimmunol.0902575
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发表时间：
2010-02-01
影响因子：
4.4
通讯作者：
Power, Christopher
中科院分区：
文献类型：
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作者：
Maingat, Ferdinand;Viappiani, Serena;Power, Christopher
包括HIV和猫免疫缺陷病毒（FIV）在内的慢病毒感染引起神经毒力，其主要由先天免疫介导。为了研究神经毒力和先天免疫激活的重复调节之间的相互作用，将慢病毒感染模型暴露于LPS。通过真实的时间RT-PCR和免疫细胞化学比较HIV感染者（HIV+）和对照（HIV-）患者脑中的基因表达。将来自暴露于LPS的模拟物和HIV感染的单核细胞衍生的巨噬细胞的上清液应用于人神经元。FIV感染（FIV+）和对照（FIV-）动物反复暴露于LPS感染后，同时进行神经行为测试，病毒载量和宿主基因分析。来自HIV+个体的脑表现出诱导CD 3 β、CXCL 10和颗粒酶A表达（p < 0.05）。来自HIV+单核细胞衍生的巨噬细胞的上清液诱导神经元中的CXCL 10表达，其被IL-10处理减弱（p < 0.05）。暴露于LPS的FIV+动物表现出较低的血浆和脑病毒载量（p < 0.05）。在FIV+动物中神经元CXCL 10表达增加，但受到LPS暴露的抑制，同时脑CD 3E和颗粒酶A表达降低（p < 0.05）。与顶叶皮质中保留的NeuN阳性神经元计数（p < 0.05）相结合，暴露于LPS的FIV+动物也显示出较不严重的神经行为缺陷（p < 0.05）。重复的LPS暴露抑制了脑中的CXCL 10和随后的T细胞浸润，伴随着神经毒力的降低。因此，先天免疫慢性条件反射通过抑制IL-10介导的特异性趋化因子CXCL 10对神经毒力产生有益影响，从而减少白细胞浸润和神经毒性因子的释放。免疫学杂志，2010，184：1566-1574。
Lentivirus infections including HIV and feline immunodeficiency virus (FIV) cause neurovirulence, which is largely mediated by innate immunity. To investigate the interactions between neurovirulence and repeated conditioning by innate immune activation, models of lentivirus infection were exposed to LPS. Gene expression in HIV-infected (HIV+) and control (HIV-) patient brains was compared by real time RT-PCR and immunocytochemistry. Supernatants from mock and HIV-infected monocyte-derived macrophages exposed to LPS were applied to human neurons. FIV-infected (FIV+) and control (FIV-) animals were exposed repeatedly to LPS postinfection together with concurrent neurobehavioral testing, viral load, and host gene analyses. Brains from HIV+ individuals exhibited induction of CD3 epsilon, CXCL10, and granzyme A expression (p < 0.05). Supernatants from HIV+ monocyte-derived macrophages induced CXCL10 expression in neurons, which was diminished by IL-10 treatment (p < 0.05). LPS-exposed FIV+ animals demonstrated lower plasma and brain viral loads (p < 0.05). Neuronal CXCL10 expression was increased in FIV+ animals but was suppressed by LPS exposure, together with reduced brain CD3E and granzyme A expression (p < 0.05). In conjunction with preserved NeuN-positive neuronal counts in parietal cortex (p < 0.05), FIV+ animals exposed to LPS also showed less severe neurobehavioral deficits (p < 0.05). Repeated LPS exposures suppressed CXCL10 in the brain and ensuing T cell infiltration with a concomitant reduction in neurovirulence. Thus, innate immune chronic conditioning exerted beneficial effects on neurovirulence through suppression of a specific chemotactic factor, CXCL10, mediated by IL-10, leading to reduced leukocyte infiltration and release of neurotoxic factors. The Journal of Immunology, 2010, 184: 1566-1574.