Oreshkova Nadia, Wichgers Schreur Paul J, Spel Lotte, Vloet Rianka P M, Moormann Rob J M, Boes Marianne, Kortekaas Jeroen
Department of Virology, Central Veterinary Institute, part of Wageningen University and Research Centre, Lelystad, The Netherlands.
Department of Infectious Diseases and Immunology, Virology Division, Faculty of Veterinary Medicine, Utrecht University, Utrecht, The Netherlands.
PLoS One. 2015 Nov 17;10(11):e0142670. doi: 10.1371/journal.pone.0142670. eCollection 2015.
Vaccines based on nonspreading Rift Valley fever virus (NSR) induce strong humoral and robust cellular immune responses with pronounced Th1 polarisation. The present work was aimed to gain insight into the molecular basis of NSR-mediated immunity. Recent studies have demonstrated that wild-type Rift Valley fever virus efficiently targets and replicates in dendritic cells (DCs). We found that NSR infection of cultured human DCs results in maturation of DCs, characterized by surface upregulation of CD40, CD80, CD86, MHC-I and MHC-II and secretion of the proinflammatory cytokines IFN-β, IL-6 and TNF. Interestingly, expression of the most prominent marker of DC maturation, CD83, was consistently downregulated at 24 hours post infection. Remarkably, NSR infection also completely abrogated CD83 upregulation by LPS. Downregulation of CD83 was not associated with reduced mRNA levels or impaired CD83 mRNA transport from the nucleus and could not be prevented by inhibition of the proteasome or endocytic degradation pathways, suggesting that suppression occurs at the translational level. In contrast to infected cells, bystander DCs displayed full maturation as evidenced by upregulation of CD83. Our results indicate that bystander DCs play an important role in NSR-mediated immunity.
基于非传播性裂谷热病毒（NSR）的疫苗可诱导强烈的体液免疫和强大的细胞免疫反应，并伴有明显的Th1极化。本研究旨在深入了解NSR介导的免疫的分子基础。最近的研究表明，野生型裂谷热病毒能有效地靶向树突状细胞（DCs）并在其中复制。我们发现，培养的人DCs感染NSR后会导致DCs成熟，其特征是CD40、CD80、CD86、MHC-I和MHC-II的表面上调以及促炎细胞因子IFN-β、IL-6和TNF的分泌。有趣的是，DC成熟的最显著标志物CD83的表达在感染后24小时持续下调。值得注意的是，NSR感染还完全消除了LPS诱导的CD83上调。CD83的下调与mRNA水平降低或CD83 mRNA从细胞核的转运受损无关，并且不能通过抑制蛋白酶体或内吞降解途径来预防，这表明抑制发生在翻译水平。与感染的细胞不同，旁观者DCs表现出完全成熟，这通过CD83的上调得到证明。我们的结果表明，旁观者DCs在NSR介导的免疫中起重要作用。
