Yamashita Nobuko, Yashiro Masato, Ogawa Hirohito, Namba Hikaru, Nosaka Nobuyuki, Fujii Yousuke, Morishima Tsuneo, Tsukahara Hirokazu, Yamada Masao
Department of Virology, Graduate School of Medicine, Dentistry, and Pharmaceutical Sciences, Okayama University, Okayama, Japan; Department of Pediatrics, Graduate School of Medicine, Dentistry, and Pharmaceutical Sciences, Okayama University, Okayama, Japan.
Department of Pediatrics, Graduate School of Medicine, Dentistry, and Pharmaceutical Sciences, Okayama University, Okayama, Japan.
Biochem Biophys Res Commun. 2017 Aug 5;489(4):466-471. doi: 10.1016/j.bbrc.2017.05.172. Epub 2017 May 30.
Our previous analysis of gene expression profiles in the peripheral blood from patients with influenza A (H1N1) pdm09 pneumonia revealed elevated transcription levels of the vanin-1 (vascular non-inflammatory molecule 1, VNN1) gene, which encodes an epithelial ectoenzyme with pantetheinase activity involved in recycling coenzyme A. Here, to elucidate the role of VNN1 in influenza A virus (IAV) H1N1 infection, we investigated the change of VNN1 expression in the context of IAV infection and the effects of its related substances, i.e., its direct substrate pantetheine and its two metabolites pantothenic acid and cysteamine on the replication of IAV in the human alveolar epithelial carcinoma cell line A549. The messenger RNA expression of VNN1 in A549 cells was significantly increased (by 4.9-fold) after IAV infection under an elevated concentration of pantetheine. Moreover, VNN1 mRNA levels were elevated by > 100-fold in response to pro-inflammatory cytokines, especially TNF-α and IL-1β. Pantetheine significantly reduced the IAV replication and IAV Matrix 1 (M1) mRNA levels when it was administered prior to and during infection. In addition, cysteamine treatment during IAV infection significantly reduced the viral replication and IAV M1 mRNA levels, whereas pantothenic acid did not. These findings suggest that the metabolic pathway catalyzed by VNN1 pantetheinase plays a suppressive role in IAV infection in the respiratory tract, especially in severe conditions under hypercytokinemia.
我们之前对甲型H1N1pdm09流感肺炎患者外周血基因表达谱的分析显示，泛酰巯基乙胺酶-1（血管非炎症分子1，VNN1）基因的转录水平升高，该基因编码一种具有泛酰巯基乙胺酶活性的上皮外切酶，参与辅酶A的循环利用。在此，为了阐明VNN1在甲型流感病毒（IAV）H1N1感染中的作用，我们研究了IAV感染情况下VNN1表达的变化及其相关物质，即其直接底物泛酰巯基乙胺及其两种代谢产物泛酸和半胱胺对IAV在人肺泡上皮癌细胞系A549中复制的影响。在泛酰巯基乙胺浓度升高的情况下，IAV感染后A549细胞中VNN1的信使核糖核酸表达显著增加（增加了4.9倍）。此外，促炎细胞因子，尤其是TNF-α和IL-1β可使VNN1信使核糖核酸水平升高100倍以上。在感染前和感染期间给予泛酰巯基乙胺，可显著降低IAV复制和IAV基质蛋白1（M1）信使核糖核酸水平。此外，在IAV感染期间给予半胱胺治疗可显著降低病毒复制和IAV M1信使核糖核酸水平，而泛酸则无此作用。这些发现表明，由VNN1泛酰巯基乙胺酶催化的代谢途径在呼吸道IAV感染中起抑制作用，尤其是在高细胞因子血症的严重情况下。
