TREM2 suppresses the proinflammatory response to facilitate PRRSV infection via PI3K/NF-κB signaling
TREM2 suppresses the proinflammatory response to facilitate PRRSV infection via PI3K/NF-κB signaling
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TREM2 通过 PI3K/NF-κB 信号传导抑制促炎反应，促进 PRRSV 感染。
DOI：
10.1371/journal.ppat.1008543
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发表时间：
2020-05-01
期刊：
影响因子：
6.7
通讯作者：
Guo, Chunhe
中科院分区：
文献类型：
--
作者：
Zhu, Zhenbang;Zhang, Xiaoxiao;Guo, Chunhe
猪繁殖与呼吸综合征病毒（Porcine reproductive and respiratory syndrome virus，PRRSV）是全球养猪业中最重要的病原之一，是一种难以控制的疾病。CD 163是PRRSV感染所需的受体，其表达受多种炎症介质调节。髓样细胞触发受体2（Triggering Receptor Expression on Myeloid Cells 2，TREM 2）是一种新型的免疫调节受体，参与天然免疫和抗炎反应。在这里，我们试图阐明TREM 2是否通过炎症反应调节CD 163表达以促进PRRSV感染。我们发现在体外和体内在感染猪的肺和淋巴结中在PRRSV感染后TREM 2水平增加。我们证明了TREM 2的胞质尾区与PRRSV Nsp 2相互作用以促进感染。此外，TREM 2沉默通过PI 3 K/NF-κ B途径触发早期促炎反应，从而下调CD 163的表达，这导致病毒抑制。我们的工作为抗PRRSV感染提供了一种新的抗病毒机制，并提示靶向TREM 2可能成为控制该病的新途径。髓样细胞表达的触发受体2（TREM 2）作为抗炎受体，负性调节先天性免疫反应。TREM 2主要表达于猪生殖与呼吸综合征病毒（PRRSV）的靶细胞--树突状细胞和巨噬细胞上。因此，我们研究了TREM 2在猪肺泡巨噬细胞（PAM）中的PRRSV感染中的潜在作用。我们发现在体外感染PRRSV后TREM 2的表达增加。TREM 2沉默抑制PRRSV的复制，而TREM 2过表达促进病毒复制。TREM 2的胞质尾部结构域与PRRSV Nsp 2相互作用以促进感染。TREM 2下调导致PI 3 K/NF-κ B信号的早期激活，从而加强促炎细胞因子和I型干扰素的表达。由于增强的细胞因子表达，去整合素和金属蛋白酶17被激活以促进膜CD 163的切割，这导致感染的抑制。此外，外源性可溶性TREM 2（sTREM 2）介导的对PRRSV附着的抑制可能归因于其与病毒包膜蛋白的竞争性结合。在猪体内，在PRRSV体内攻击后，肺和淋巴结中TREM 2的表达以及sTREM 2的产生显著增加。这些新的发现表明TREM 2通过炎症反应在调节PRRSV复制中起作用。因此，我们的工作描述了一种新的抗PRRSV感染的抗病毒机制，并表明靶向TREM 2可能是控制PRRSV感染的新方法。
Author summaryPorcine reproductive and respiratory syndrome virus (PRRSV) is one of the most important pathogens in the global swine industry and is difficult to control. CD163 is a receptor that is required for PRRSV infection, and its expression is regulated by various inflammatory mediators. Triggering receptor expressed on myeloid cells 2 (TREM2) is a novel immunoregulatory receptor, which is involved in innate immunity and anti-inflammatory responses. Here we sought to elucidate whether TREM2 regulates CD163 expression to promote PRRSV infection via the inflammatory response. We found increased TREM2 levels upon PRRSV infection in vitro and in vivo in the lungs and lymph nodes of infected pigs. We demonstrated that the cytoplasmic tail of TREM2 interacts with PRRSV Nsp2 to promote infection. Additionally, TREM2 silencing triggers an early proinflammatory response via PI3K/NF-kappa B pathway, thus downregulating the expression of CD163, which leads to virus suppression. Our work provides a novel antiviral mechanism against PRRSV infection and suggests that targeting TREM2 could be a new approach for control of the disease.Triggering receptor expressed on myeloid cells 2 (TREM2) serves as an anti-inflammatory receptor, negatively regulating the innate immune response. TREM2 is mainly expressed on dendritic cells and macrophages, the target cells of porcine reproductive and respiratory syndrome virus (PRRSV). Thus, we investigated the potential role of TREM2 in PRRSV infection in porcine alveolar macrophages (PAMs). We found that there was an increased expression of TREM2 upon PRRSV infection in vitro. TREM2 silencing restrained the replication of PRRSV, whereas TREM2 overexpression facilitated viral replication. The cytoplasmic tail domain of TREM2 interacted with PRRSV Nsp2 to promote infection. TREM2 downregulation led to early activation of PI3K/NF-kappa B signaling, thus reinforcing the expression of proinflammatory cytokines and type I interferons. Due to the enhanced cytokine expression, a disintegrin and metalloproteinase 17 was activated to promote the cleavage of membrane CD163, which resulted in suppression of infection. Furthermore, exogenous soluble TREM2 (sTREM2)-mediated inhibition of PRRSV attachment might be attributed to its competitive binding to viral envelope proteins. In pigs, following PRRSV challenge in vivo, the expression of TREM2 in lungs and lymph nodes as well as the production of sTREM2 were significantly increased. These novel findings indicate that TREM2 plays a role in regulating PRRSV replication via the inflammatory response. Therefore, our work describes a novel antiviral mechanism against PRRSV infection and suggests that targeting TREM2 could be a new approach in the control of the PRRSV infection.