Ahmed Chulbul M, Johnson Howard M
University of Florida, Department of Microbiology and Cell Science, Gainesville, Florida, USA.
University of Florida, Department of Microbiology and Cell Science, Gainesville, Florida, USA
Clin Vaccine Immunol. 2014 Aug;21(8):1178-84. doi: 10.1128/CVI.00204-14. Epub 2014 Jun 25.
The canonical model of interferon (IFN) signaling focuses solely on the activation of STAT transcription factors which, according to the model, are initiated by the singular event of cross-linkage of the receptor extracellular domain by the IFN. The IFN has no further function beyond this. The model thus provides no approach to circumventing poxviruses decoy receptors that compete with the IFN receptors for IFNs. This simple event has allowed smallpox virus to decimate human populations throughout the ages. We have developed a noncanonical model of IFN signaling that has resulted in the development of small peptide mimetics to both types I and II IFNs. In this report, we focus on a type I IFN mimetic at positions 152 to 189, IFN-α1(152-189), which corresponds to the C terminus of human IFN-α1. This mimetic functions intracellularly and is thus not recognized by the B18R vaccinia virus decoy receptor. Mimetic synthesized with an attached palmitate (lipo-) for cell penetration protects mice from a lethal dose of vaccinia virus, while the parent IFN-α1 is ineffective. Unlike IFN-α1, the mimetic does not bind to the B18R decoy receptor. It further differs from the parent IFN in that it lacks the toxicity of weight loss and bone marrow suppression in mice while at the same time possessing a strong adjuvant effect on the immune system. The mimetic is thus an innate and adaptive immune regulator that is evidence of the dynamic nature of the noncanonical model of IFN signaling, in stark contrast to the canonical or classical model of signaling.
干扰素（IFN）信号传导的经典模型仅关注STAT转录因子的激活，根据该模型，这是由IFN使受体细胞外结构域交联这一单事件引发的。在此之外，IFN没有其他功能。因此，该模型没有提供规避痘病毒诱饵受体的方法，这些诱饵受体与IFN受体竞争IFN。这一简单事件使得天花病毒在各个时代都能大量杀死人类。我们已经开发出一种IFN信号传导的非经典模型，由此研发出了针对I型和II型IFN的小肽模拟物。在本报告中，我们聚焦于位于152至189位的I型IFN模拟物，即IFN-α1(152 - 189)，它对应于人IFN-α1的C末端。这种模拟物在细胞内发挥作用，因此不会被牛痘病毒B18R诱饵受体识别。合成的带有用于细胞穿透的棕榈酸酯（脂质化）的模拟物能保护小鼠免受致死剂量的牛痘病毒感染，而亲本IFN-α1则无效。与IFN-α1不同，该模拟物不与B18R诱饵受体结合。它与亲本IFN的进一步区别在于，它在小鼠中没有体重减轻和骨髓抑制的毒性，同时对免疫系统具有强大的佐剂效应。因此，该模拟物是一种先天性和适应性免疫调节剂，这证明了IFN信号传导非经典模型的动态性质，与经典信号传导模型形成鲜明对比。
