Herpes Simplex Virus Type-2 Paralyzes the Function of Monocyte-Derived Dendritic Cells
Herpes Simplex Virus Type-2 Paralyzes the Function of Monocyte-Derived Dendritic Cells
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DOI：
10.3390/v12010112
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发表时间：
2020-01-01
期刊：
影响因子：
4.7
通讯作者：
Heilingloh, Christiane Silke
中科院分区：
文献类型：
--
作者：
Grosche, Linda;Muehl-Zuerbes, Petra;Heilingloh, Christiane Silke
单纯疱疹病毒不仅感染各种不同的细胞类型，包括树突状细胞（DC），而且还调节重要的细胞功能，使病毒受益。鉴于在有效的抗病毒免疫应答的起始期间定向免疫细胞迁移的相关性，干扰DC迁移构成阻碍抗病毒免疫的复杂策略。值得注意的是，最近的报道显示HSV-1在体外显著抑制DC迁移。因此，我们旨在研究HSV-2是否也调节DC生物学的不同标志。在这里，我们证明，HSV-2负干扰趋化因子依赖的成熟DC（mDC）的体外迁移能力。有趣的是，HSV-2不是在感染早期介导同源趋化因子受体表达的减少，而是快速诱导β 2整联蛋白（LFA-1）介导的mDC粘附，从而阻断mDC迁移。从机制上讲，HSV-2触发β 2整联蛋白活性的负调节因子CYTIP的蛋白酶体降解，这导致LFA-1的组成性激活，从而导致mDC粘附。总之，我们的数据扩展并加强了最近的研究结果，报告在疱疹病毒感染的背景下减少了mDC迁移。因此，我们假设，通过抑制mDC迁移来阻碍抗原递送至次级淋巴器官是疱疹病毒科不同成员之间的进化保守策略。
Herpes simplex viruses not only infect a variety of different cell types, including dendritic cells (DCs), but also modulate important cellular functions in benefit of the virus. Given the relevance of directed immune cell migration during the initiation of potent antiviral immune responses, interference with DC migration constitutes a sophisticated strategy to hamper antiviral immunity. Notably, recent reports revealed that HSV-1 significantly inhibits DC migration in vitro. Thus, we aimed to investigate whether HSV-2 also modulates distinct hallmarks of DC biology. Here, we demonstrate that HSV-2 negatively interferes with chemokine-dependent in vitro migration capacity of mature DCs (mDCs). Interestingly, rather than mediating the reduction of the cognate chemokine receptor expression early during infection, HSV-2 rapidly induces beta 2 integrin (LFA-1)-mediated mDC adhesion and thereby blocks mDC migration. Mechanistically, HSV-2 triggers the proteasomal degradation of the negative regulator of beta 2 integrin activity, CYTIP, which causes the constitutive activation of LFA-1 and thus mDC adhesion. In conclusion, our data extend and strengthen recent findings reporting the reduction of mDC migration in the context of a herpesviral infection. We thus hypothesize that hampering antigen delivery to secondary lymphoid organs by inhibition of mDC migration is an evolutionary conserved strategy among distinct members of Herpesviridae.