HSV-1 Modulates IL-6 Receptor Expression on Human Dendritic Cells
HSV-1 Modulates IL-6 Receptor Expression on Human Dendritic Cells
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DOI：
10.3389/fimmu.2020.01970
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发表时间：
2020-08-26
影响因子：
7.3
通讯作者：
Popella, Linda
中科院分区：
文献类型：
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作者：
Birzer, Alexandra;Krawczyk, Adalbert;Popella, Linda
树突状细胞(DC)是免疫系统的守护者，因为它们位于大多数外周组织中。此外，基于它们刺激幼稚T细胞的独特能力，它们对于诱导有效的免疫反应至关重要。在共同进化过程中，人类病原体单纯疱疹病毒1型(HSV-1)已经进化出几种免疫逃避机制，以破坏宿主的免疫系统，特别是通过靶向DC的生物学和功能。在这里，我们证明了HSV-1感染对人单核细胞来源的成熟DC(MDCs)的IL-6受体(IL-6R)蛋白和mRNA表达的影响。令人惊讶的是，在未感染的旁观者MDCS上也观察到IL6R表达水平降低。从机制上，我们清楚地证明了单纯疱疹病毒1型非传染性光(L-)颗粒足以触发IL6R对未感染的旁观者MDCS的调节。这些L颗粒缺乏携带病毒DNA的衣壳，主要在MDCS感染期间产生。我们的结果表明，HSV-1被膜蛋白VHS的缺失部分挽救了旁观者MDCS表面IL6R表达水平的降低。使用中和抗体干扰L颗粒向旁观者mDCs的转运，足以挽救未感染的旁观者mDCs对IL6R表面表达的调节。这项研究提供了证据，L颗粒将特定的病毒蛋白转移到未感染的旁观者MDCS，从而对其IL6R表达水平产生负面干扰，但与H颗粒相比，干扰程度较小。由于其免疫调节能力，L颗粒代表了HSV-1介导的免疫逃避的一种精心设计的方法。
Dendritic cells (DCs) are the guardians of the immune system since they are located in the majority of peripheral tissues. In addition, they are crucial for the induction of an effective immune response based on their unique capacity to stimulate naive T cells. During co-evolution, the human pathogen herpes simplex virus type 1 (HSV-1) has evolved several immune evasion mechanisms in order to subvert the host's immune system especially by targeting DC biology and function. Here we demonstrate that HSV-1 infection influences the IL-6 receptor (IL6R) expression both on protein and mRNA levels in/on human monocyte-derived mature DCs (mDCs). Surprisingly, reduced IL6R expression levels were also observed on uninfected bystander mDCs. Mechanistically, we clearly show that HSV-1-derived non-infectious light (L-) particles are sufficient to trigger IL6R regulation on uninfected bystander mDCs. These L-particles lack the viral DNA-loaded capsid and are predominantly produced during infection of mDCs. Our results show that the deletion of the HSV-1 tegument protein vhs partially rescued the reduced IL6R surface expression levels on/in bystander mDCs. Using a neutralizing antibody, which perturbs the transfer of L-particles to bystander mDCs, was sufficient to rescue the modulation of IL6R surface expression on uninfected bystander mDCs. This study provides evidence that L-particles transfer specific viral proteins to uninfected bystander mDCs, thereby negatively interfering with their IL6R expression levels, however, to a lesser extend compared to H-particles. Due to their immune-modulatory capacity, L-particles represent an elaborated approach of HSV-1-mediated immune evasion.