Epstein-Barr virus infection-induced inflammasome activation in human monocytes.
Epstein-Barr virus infection-induced inflammasome activation in human monocytes.
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DOI：
10.1371/journal.pone.0175053
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发表时间：
2017
期刊：
影响因子：
3.7
通讯作者：
Ito Y
中科院分区：
文献类型：
--
作者：
Torii Y;Kawada JI;Murata T;Yoshiyama H;Kimura H;Ito Y
炎性小体是细胞质传感器，调节caspase-1的活性和白细胞介素-1β (IL-1β)或白细胞介素-18 （IL-18）的分泌，以应对外来分子，包括病毒病原体。它们被认为是先天免疫反应和适应性免疫反应之间的重要联系。然而，在原发性eb病毒（EBV）感染期间，炎性体激活的机制尚不清楚。人类B淋巴细胞和上皮细胞是EBV的主要目标，尽管它也可以感染多种其他细胞类型。在本研究中，我们发现EBV可以感染原代人单核细胞和单核细胞系THP-1，诱导炎性体活化。我们将无细胞EBV与THP-1细胞或原代人单核细胞孵育，然后用共聚焦显微镜和流式细胞术证实EBV感染。实时RT-PCR检测EBV感染单核细胞的裂解和潜伏基因。EBV感染THP-1细胞和原代人单核细胞诱导caspase依赖性IL-1β的产生，而EBV感染b细胞或t细胞系不诱导IL-1β的产生。为了确定EBV感染期间负责炎症小体激活的传感器分子，我们检测了黑色素瘤2 （AIM2）中缺失的NLR家族pyrin结构域3 （NLRP3）和干扰素诱导蛋白16 （IFI16）的mRNA和蛋白水平。在ebv感染的THP-1细胞和原代人单核细胞中，AIM2水平升高，而IFI16和NLRP3水平无显著变化。此外，通过小干扰RNA敲除AIM2可减弱caspase-1的激活。综上所述，我们的研究结果表明EBV感染人类单核细胞诱导caspase-1依赖性IL-1β产生，而AIM2作为炎症小体参与了这一反应。
Inflammasomes are cytoplasmic sensors that regulate the activity of caspase-1 and the secretion of interleukin-1β (IL-1β) or interleukin-18 (IL-18) in response to foreign molecules, including viral pathogens. They are considered to be an important link between the innate and adaptive immune responses. However, the mechanism by which inflammasome activation occurs during primary Epstein-Barr virus (EBV) infection remains unknown. Human B lymphocytes and epithelial cells are major targets of EBV, although it can also infect a variety of other cell types. In this study, we found that EBV could infect primary human monocytes and the monocyte cell line, THP-1, inducing inflammasome activation. We incubated cell-free EBV with THP-1 cells or primary human monocytes, then confirmed EBV infection using confocal microscopy and flow cytometry. Lytic and latent EBV genes were detected by real-time RT-PCR in EBV-infected monocytes. EBV infection of THP-1 cells and primary human monocytes induced caspase-dependent IL-1β production, while EBV infection of B-cell or T-cell lines did not induce IL-1β production. To identify the sensor molecule responsible for inflammasome activation during EBV infection, we examined the mRNA and the protein levels of NLR family pyrin domain-containing 3 (NLRP3), absent in melanoma 2 (AIM2), and interferon-inducible protein 16 (IFI16). Increased AIM2 levels were observed in EBV-infected THP-1 cells and primary human monocytes, whereas levels of IFI16 and NLRP3 did not show remarkable change. Furthermore, knockdown of AIM2 by small interfering RNA attenuated caspase-1 activation. Taken together, our results suggest that EBV infection of human monocytes induces caspase-1-dependent IL-1β production, and that AIM2, acting as an inflammasome, is involved in this response.