Role of DC-SIGN in Lassa Virus Entry into Human Dendritic Cells
Role of DC-SIGN in Lassa Virus Entry into Human Dendritic Cells
复制标题
DOI：
10.1128/jvi.01893-13
复制
发表时间：
2013-11-01
影响因子：
5.4
通讯作者：
Kunz, Stefan
中科院分区：
文献类型：
--
作者：
Goncalves, Ana-Rita;Moraz, Marie-Laurence;Kunz, Stefan
阿雷纳病毒拉萨病毒(LASV)在人类中引起严重的出血热，死亡率很高。抗原提呈细胞，特别是树突状细胞(DC)，是LASV的早期和首选靶点，其生产性感染有助于在致命疾病中观察到病毒诱导的免疫抑制。在这里，我们利用表达LASV糖蛋白的原型ArenaVirus淋巴细胞性脉络膜脑膜炎病毒(LCMV)的嵌合体，研究了C型凝集素DC特异性ICAM-3抓取非整合素(DC-SIGN)在LASV进入原代人类DC中的作用。我们发现，人原代单核细胞分化为树突状细胞可以增强病毒的附着和进入，同时伴随着DC-SIGN的上调。LASV和rLCMV-LASVGP通过位于LASVGP的N端GP1亚基上的甘露糖与DC-SIGN结合。我们提供的证据表明，DC-SIGN作为rLCMV-LASVGP在单核细胞来源的未成熟树突状细胞(MDDC)中的附着因子，可以加速游离病毒的捕获。然而，与使用DC-SIGN作为真实进入受体的细小病毒Uukuniemi病毒(UUKV)不同，rLCMV-LASVGP的生产性感染对DC-SIGN的依赖性较低。与DC-SIGN介导的UUKV细胞进入不同，rLCMV-LASVGP进入MDDC的速度非常缓慢，并依赖于肌动蛋白，这表明使用了不同的内吞途径。综上所述，我们的数据显示DC-SIGN可以促进LASV在人MDDC中的细胞进入，但它的作用似乎与已报道的作为静脉病毒的真实进入受体的功能不同。
The arenavirus Lassa virus (LASV) causes a severe hemorrhagic fever with high mortality in humans. Antigen-presenting cells, in particular dendritic cells (DCs), are early and preferred targets of LASV, and their productive infection contributes to the virus-induced immunosuppression observed in fatal disease. Here, we characterized the role of the C-type lectin DC-specific ICAM-3-grabbing nonintegrin (DC-SIGN) in LASV entry into primary human DCs using a chimera of the prototypic arenavirus lymphocytic choriomeningitis virus (LCMV) expressing the LASV glycoprotein (rLCMV-LASVGP). We found that differentiation of human primary monocytes into DCs enhanced virus attachment and entry, concomitant with the upregulation of DC-SIGN. LASV and rLCMV-LASVGP bound to DC-SIGN via mannose sugars located on the N-terminal GP1 subunit of LASVGP. We provide evidence that DC-SIGN serves as an attachment factor for rLCMV-LASVGP in monocyte-derived immature dendritic cells (MDDC) and can accelerate the capture of free virus. However, in contrast to the phlebovirus Uukuniemi virus (UUKV), which uses DC-SIGN as an authentic entry receptor, productive infection with rLCMV-LASVGP was less dependent on DC-SIGN. In contrast to the DC-SIGN-mediated cell entry of UUKV, entry of rLCMV-LASVGP in MDDC was remarkably slow and depended on actin, indicating the use of different endocytotic pathways. In sum, our data reveal that DC-SIGN can facilitate cell entry of LASV in human MDDC but that its role seems distinct from the function as an authentic entry receptor reported for phleboviruses.