Middle east respiratory syndrome corona virus spike glycoprotein suppresses macrophage responses via DPP4-mediated induction of IRAK-M and PPARγ.
Middle east respiratory syndrome corona virus spike glycoprotein suppresses macrophage responses via DPP4-mediated induction of IRAK-M and PPARγ.
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DOI：
10.18632/oncotarget.14754
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发表时间：
2017-02-07
期刊：
影响因子：
--
通讯作者：
Tsatsanis C
中科院分区：
文献类型：
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作者：
Al-Qahtani AA;Lyroni K;Aznaourova M;Tseliou M;Al-Anazi MR;Al-Ahdal MN;Alkahtani S;Sourvinos G;Tsatsanis C
中东呼吸综合征冠状病毒（MERS-CoV）通过呼吸道传播，并通过感染肺上皮细胞和巨噬细胞引起严重的急性呼吸窘迫综合征。MERS-CoV通过其刺突（S）糖蛋白感染细胞，该糖蛋白结合存在于巨噬细胞上的二肽基肽酶4（DPP 4）受体。这种刺突/DPP 4结合是否影响巨噬细胞反应仍然未知。在本文中，我们证明了用MERS-CoV S糖蛋白假型化的慢病毒颗粒感染巨噬细胞导致巨噬细胞应答的抑制，因为它降低了巨噬细胞在幼稚和LPS激活的THP-1巨噬细胞中产生TNF α和IL-6的能力，并增强了LPS诱导的免疫抑制细胞因子IL-10的产生。MERS-CoV S糖蛋白诱导TLR信号传导负调节因子IRAK-M以及转录抑制因子PPARγ的表达。通过其抑制剂西格列汀或siRNA抑制DPP 4可消除MERS-CoV S糖蛋白对IRAK-M、PPARγ和IL-10的作用，证实其免疫抑制作用是由DPP 4受体介导的。在THP-1巨噬细胞和人原代外周血单核细胞中均观察到该作用。这些发现支持了巨噬细胞中DPP 4介导的MERS-CoV抑制作用，并提出了有效消除其致病性的潜在靶点。
Middle East Respiratory Syndrome Corona Virus (MERS-CoV) is transmitted via the respiratory tract and causes severe Acute Respiratory Distress Syndrome by infecting lung epithelial cells and macrophages. Macrophages can readily recognize the virus and eliminate it. MERS-CoV infects cells via its Spike (S) glycoprotein that binds on Dipeptidyl-Peptidase 4 (DPP4) receptor present on macrophages. Whether this Spike/DPP4 association affects macrophage responses remains unknown. Herein we demonstrated that infection of macrophages with lentiviral particles pseudotyped with MERS-CoV S glycoprotein results in suppression of macrophage responses since it reduced the capacity of macrophages to produce TNFa and IL-6 in naive and LPS-activated THP-1 macrophages and augmented LPS-induced production of the immunosuppressive cytokine IL-10. MERS-CoV S glycoprotein induced the expression of the negative regulator of TLR signaling IRAK-M as well as of the transcriptional repressor PPARγ. Inhibition of DPP4 by its inhibitor sitagliptin or siRNA abrogated the effects of MERS-CoV S glycoprotein on IRAK-M, PPARγ and IL-10, confirming that its immunosuppressive effects were mediated by DPP4 receptor. The effect was observed both in THP-1 macrophages and human primary peripheral blood monocytes. These findings support a DPP4-mediated suppressive action of MERS-CoV in macrophages and suggest a potential target for effective elimination of its pathogenicity.