Interferon gamma modulation of disease manifestation and the local antibody response to alphavirus encephalomyelitis
Interferon gamma modulation of disease manifestation and the local antibody response to alphavirus encephalomyelitis
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DOI：
10.1099/jgv.0.000613
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发表时间：
2016-11-01
影响因子：
3.8
通讯作者：
Griffin, Diane E.
中科院分区：
文献类型：
--
作者：
Baxter, Victoria K.;Griffin, Diane E.
感染辛德比斯病毒（SINV）的小鼠会产生脑脊髓炎，并为检查中枢神经系统（CNS）对甲病毒感染的免疫反应提供了模型。感染性病毒的清除是通过 SINV 特异性抗体和 IFN-γ 之间的合作来完成的，但人们对其中的调节相互作用知之甚少。为了确定 IFN-γ 对临床疾病和抗病毒免疫反应的影响，对缺乏 IFN-γ (Ifng(-/-)) 或 IFN-γ 受体 (Ifngr1(-/-)) 的 C57BL/6 小鼠进行了与 WT 小鼠比较的研究。 WT和Ifngr1(-/-)小鼠中枢神经系统中Ifng mRNA和IFN-gamma蛋白的最大产量发生在感染后5-7天，其中Ifngr1(-/-)小鼠中IFN-g水平较高。 IFN-gamma 信号受损的小鼠临床疾病发病较早，但 Ifngr1(-/-) 小鼠恢复得更快。 Ifng(-/-) 和 Ifngr1(-/-) 小鼠比 WT 小鼠更好地保持体重，这与更好的食物摄入和更低的脑炎性细胞因子水平有关。与 WT 小鼠相比，Ifngr1(-/-) 和 Ifng(-/-) 小鼠的脊髓中感染性病毒的清除速度较慢，CNS（而非血清）SINV 特异性 IgM、IgG2a 和 IgG2b 水平较低。 CNS 抗病毒抗体减少与 B 细胞吸引趋化因子 CXCL9、CXCL10 和 CXCL13 的 mRNA 表达降低以及 CNS 中 B 细胞减少有关。因此，IFN-γ信号传导增加了 CNS 促炎细胞因子的水平，导致临床疾病，但至少部分通过增加对分泌抗体的 B 细胞浸润到 CNS 中重要的趋化因子产生来协同清除病毒与 SINV 特异性抗体。
Infection of mice with Sindbis virus (SINV) produces encephalomyelitis and provides a model for examination of the central nervous system (CNS) immune response to alphavirus infection. Clearance of infectious virus is accomplished through a cooperative effort between SINV-specific antibody and IFN-gamma, but the regulatory interactions are poorly understood. To determine the effects of IFN-gamma on clinical disease and the antiviral immune response, C57BL/6 mice lacking IFN-gamma (Ifng(-/-)) or IFN-gamma receptor (Ifngr1(-/-)) were studied in comparison to WT mice. Maximum production of Ifng mRNA and IFN-gamma protein in the CNS of WT and Ifngr1(-/-) mice occurred 5-7 days after infection, with higher levels of IFN-g in Ifngr1(-/-) mice. Onset of clinical disease was earlier in mice with impaired IFN-gamma signalling, although Ifngr1(-/-) mice recovered more rapidly. Ifng(-/-) and Ifngr1(-/-) mice maintained body weight better than WT mice, associated with better food intake and lower brain levels of inflammatory cytokines. Clearance of infectious virus from the spinal cords was slower, and CNS, but not serum, levels of SINV-specific IgM, IgG2a and IgG2b were lower in Ifngr1(-/-) and Ifng(-/-) mice compared to WT mice. Decreased CNS antiviral antibody was associated with lower expression of mRNAs for B-cell attracting chemokines CXCL9, CXCL10 and CXCL13 and fewer B cells in the CNS. Therefore, IFN-gamma signalling increases levels of CNS pro-inflammatory cytokines, leading to clinical disease, but synergistically clears virus with SINV-specific antibody at least in part by increasing chemokine production important for infiltration of antibody-secreting B cells into the CNS.