Innate Immunity and Pathogenesis Unit, Laboratory of Virology, Rocky Mountain Laboratories, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Hamilton, MT 59840.
J Immunol. 2014 Mar 15;192(6):2744-55. doi: 10.4049/jimmunol.1302110. Epub 2014 Feb 14.
Tick-borne encephalitis virus (TBEV), a member of the Flaviviridae family, is a leading cause of viral encephalitis in Europe and Asia. Dendritic cells (DCs), as early cellular targets of infection, provide an opportunity for flaviviruses to inhibit innate and adaptive immune responses. Flaviviruses modulate DC function, but the mechanisms underpinning this are not defined. We examined the maturation phenotype and function of murine bone marrow-derived DCs infected with Langat virus (LGTV), a naturally attenuated member of the TBEV serogroup. LGTV infection failed to induce DC maturation or a cytokine response. Treatment with LPS or LPS/IFN-γ, strong inducers of inflammatory cytokines, resulted in enhanced TNF-α and IL-6 production, but suppressed IL-12 production in infected DCs compared with uninfected "bystander" cells or mock-infected controls. LGTV-mediated antagonism of type I IFN (IFN-I) signaling contributed to inhibition of IL-12p40 mRNA expression at late time points after stimulation. However, early suppression was still observed in DCs lacking the IFN-I receptor (Ifnar(-/-)), suggesting that additional mechanisms of antagonism exist. The early IFN-independent inhibition of IL-12p40 was nearly abolished in DCs deficient in IFN regulatory factor-1 (IRF-1), a key transcription factor required for IL-12 production. LGTV infection did not affect Irf-1 mRNA expression, but rather diminished IRF-1 protein levels and nuclear localization. The effect on IRF-1 was also observed in DCs infected with the highly virulent Sofjin strain of TBEV. Thus, antagonism of IRF-1 is a novel mechanism that synergizes with the noted ability of flaviviruses to suppress IFN-α/β receptor-dependent signaling, resulting in the orchestrated evasion of host innate immunity.
蜱传脑炎病毒（TBEV）是黄病毒科的一员，是欧洲和亚洲病毒性脑炎的主要病因。树突状细胞（DC）作为感染的早期细胞靶标，为黄病毒抑制先天和适应性免疫反应提供了机会。黄病毒调节 DC 功能，但这种调节的机制尚不清楚。我们研究了感染朗格特病毒（LGTV）的鼠骨髓来源的 DC 的成熟表型和功能，LGTV 是 TBEV 血清群中一种天然减毒的成员。LGTV 感染不能诱导 DC 成熟或细胞因子反应。用 LPS 或 LPS/IFN-γ处理，这是强烈诱导炎症细胞因子的诱导剂，导致感染的 DC 中 TNF-α 和 IL-6 的产生增加，但与未感染的“旁观者”细胞或模拟感染的对照相比，IL-12 的产生受到抑制。LGTV 介导的 I 型干扰素（IFN-I）信号转导拮抗作用导致刺激后晚期 IL-12p40 mRNA 表达的抑制。然而，在缺乏 IFN-I 受体（Ifnar(-/-)）的 DC 中仍然观察到早期抑制，这表明存在其他拮抗机制。在缺乏 IFN 调节因子-1（IRF-1）的 DC 中，早期 IFN 独立的 IL-12p40 抑制几乎被消除，IRF-1 是 IL-12 产生所必需的关键转录因子。LGTV 感染不会影响 Irf-1 mRNA 表达，但会降低 IRF-1 蛋白水平和核定位。在感染 TBEV 高度毒力的 Sofjin 株的 DC 中也观察到了这种效应。因此，IRF-1 的拮抗作用是一种新的机制，与黄病毒抑制 IFN-α/β 受体依赖性信号转导的能力协同作用，导致宿主先天免疫的协调逃避。
