Role of human β-defensin-2 during tumor necrosis factor-α/NF-κB- mediated innate antiviral response against human respiratory syncytial virus
Role of human β-defensin-2 during tumor necrosis factor-α/NF-κB- mediated innate antiviral response against human respiratory syncytial virus
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DOI：
10.1074/jbc.m710415200
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发表时间：
2008-08-15
影响因子：
4.8
通讯作者：
Bose, Santanu
中科院分区：
文献类型：
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作者：
Kota, Srikanth;Sabbah, Ahmed;Bose, Santanu
人类呼吸道合胞病毒(RSV)是一种感染肺上皮细胞引起多种呼吸道疾病的高致病性病毒。我们最近的研究发现，针对RSV存在一种不依赖干扰素α/β的先天抗病毒反应，这种反应依赖于核因子-kappaB的激活。我们证明，核因子-kappa B诱导的促炎细胞因子如肿瘤坏死因子-α(TNF)以依赖于核因子-kappa B的方式赋予抗呼吸道合胞病毒的强大抗病毒功能，而不依赖于干扰素-α/β。在研究这一途径的过程中，我们发现人β-防御素-2(HBD2)是一种可溶性的分泌型阳离子蛋白，在依赖于核因子-kappa B的人肺上皮细胞天然抗病毒活性过程中诱导产生抗病毒因子。我们的结果表明，HBD2是由肿瘤坏死因子和呼吸道合胞病毒以依赖于核因子-kappaB的方式诱导的。感染细胞中HBD2的诱导是由RSV感染时产生的肿瘤坏死因子的旁分泌/自分泌作用所介导的。HBD2在宿主防御中起着关键作用，因为纯化的HBD2能显著抑制RSV的感染。我们还表明，HBD2的抗病毒机制包括阻止病毒细胞进入，可能是因为病毒被膜的不稳定/解体。通过短干扰RNA沉默HBD2，肿瘤坏死因子的抗病毒活性的丧失也证明了HBD2在先天反应中的重要作用。在RSV感染的小鼠肺组织中，通过诱导小鼠的β-防御素-4(HBD2的小鼠对应物)，HBD2在宿主防御中的生理相关性是明显的。因此，在依赖于核因子-kappaB的天然抗病毒免疫中，HBD2起到了抗病毒分子的作用，这是通过肿瘤坏死因子的自分泌/旁分泌作用来实现的。
Human respiratory syncytial virus (RSV) constitutes a highly pathogenic virus that infects lung epithelial cells to cause a wide spectrum of respiratory diseases. Our recent studies have revealed the existence of an interferon-alpha/beta-independent, innate antiviral response against RSV that was dependent on activation of NF-kappa B. We demonstrated that NF-kappa B inducing pro-inflammatory cytokines like tumor necrosis factor-alpha(TNF) confers potent antiviral function against RSV in an NF-kappa B-dependent fashion, independent of interferon-alpha/beta. During our efforts to study this pathway, we identified HBD2 (human beta-defensin-2), a soluble secreted cationic protein as an antiviral factor induced during NF-kappa B-dependent innate antiviral activity in human lung epithelial cells. Our results demonstrated that HBD2 is induced by TNF and RSV in an NF-kappa B-dependent manner. Induction of HBD2 in infected cells was mediated by the paracrine/autocrine action of TNF produced upon RSV infection. HBD2 plays a critical role during host defense, because purified HBD2 drastically inhibited RSV infection. We also show that the antiviral mechanism of HBD2 involves blocking of viral cellular entry possibly because of destabilization/disintegration of the viral envelope. The important role of HBD2 in the innate response was also evident from loss of antiviral activity of TNF upon HBD2 silencing by short interfering RNA. The in vivo physiological relevance of HBD2 in host defense was apparent from induction of murine beta-defensin-4 (murine counterpart of HBD2) in lung tissues of RSV-infected mice. Thus, HBD2 functions as an antiviral molecule during NF-kappa B-dependent innate antiviral immunity mediated by the autocrine/paracrine action of TNF.