Department of Microbiology and Immunology, University of Melbourne at the Peter Doherty Institute for Infection and Immunity, Parkville, Victoria, Australia.
Commonwealth Science and Industrial Research Organisation, Health & Biosecurity, Australian Centre for Disease Preparedness, East Geelong, Victoria, Australia.
J Virol. 2021 Jun 24;95(14):e0011121. doi: 10.1128/JVI.00111-21.
The current fears of a future influenza pandemic have resulted in an increased emphasis on the development and testing of novel therapeutic strategies against the virus. Fundamental to this is the ferret model of influenza infection, which is critical in examining pathogenesis and treatment. Nevertheless, a precise evaluation of the efficacy of any treatment strategy in ferrets is reliant on understanding the immune response in this model. Interferon-inducible transmembrane proteins (IFITMs) are interferon-stimulated proteins shown to be critically important in the host immune response against viral infections. These proteins confer intrinsic innate immunity to pH-dependent viruses such as influenza viruses and can inhibit cytosolic entry of such viruses to limit the severity of infection following interferon upregulation. Mutations in IFITM genes in humans have been identified as key risk factors for worsened disease progression, particularly in the case of avian influenza viruses such as H7N9. While the IFITM genes of humans and mice have been well characterized, no studies have been conducted to classify the IFITM locus and interferon-driven upregulation of IFITMs in ferrets. Here, we show the architecture of the ferret IFITM locus and its synteny to the IFITM locus of other mammalian and avian species. Furthermore, we show that ferret , -, and - are functionally responsive to both interferon-α (IFN-α) and influenza virus stimulation. Thus, we show that ferret IFITMs exhibit interferon-stimulated properties similar to those shown in other species, furthering our knowledge of the innate immune response in the ferret model of human influenza virus infections. IFITM proteins can prevent the entry of several pH-dependent viruses, including high-consequence viruses such as HIV, influenza viruses, and SARS-coronaviruses. Mutations in these genes have been associated with worsened disease outcomes with mutations in their IFITM genes, highlighting these genes as potential disease risk factors. Ferrets provide a valuable tool to model infectious diseases; however, there is a critical shortage of information regarding their interferon-stimulated genes. We identified the putative ferret IFITM genes and mapped their complete gene locus. Thus, our study fills a critical gap in knowledge and supports the further use of the ferret model to explore the importance of IFITMs in these important diseases.
目前对未来流感大流行的担忧导致人们更加重视针对该病毒的新型治疗策略的开发和测试。这方面的基础是流感感染的雪貂模型，该模型在研究发病机制和治疗方法方面至关重要。然而，要准确评估任何治疗策略在雪貂中的疗效，就必须了解该模型中的免疫反应。干扰素诱导跨膜蛋白（IFITMs）是干扰素刺激的蛋白，被证明在宿主抗病毒感染的免疫反应中至关重要。这些蛋白赋予了依赖 pH 的病毒（如流感病毒）内在的先天免疫，并且可以抑制这些病毒进入细胞质，从而在干扰素上调后限制感染的严重程度。在人类中，IFITM 基因突变已被确定为疾病恶化的关键风险因素，尤其是在 H7N9 等禽流感病毒的情况下。虽然人类和小鼠的 IFITM 基因已经得到了很好的描述，但尚未对雪貂 IFITM 基因座及其干扰素驱动的 IFITM 上调进行分类。在这里，我们展示了雪貂 IFITM 基因座的结构及其与其他哺乳动物和禽类 IFITM 基因座的同源性。此外，我们还表明，雪貂的 、 和 对干扰素-α（IFN-α）和流感病毒刺激均具有功能响应。因此，我们表明雪貂 IFITM 表现出与其他物种相似的干扰素刺激特性，进一步了解了雪貂感染人类流感病毒模型中的固有免疫反应。IFITM 蛋白可以阻止几种依赖 pH 的病毒的进入，包括高后果病毒，如 HIV、流感病毒和 SARS 冠状病毒。这些基因中的突变与这些基因的 IFITM 突变相关的疾病结局恶化有关，突出了这些基因作为潜在疾病风险因素的作用。雪貂为模拟传染病提供了有价值的工具；然而，关于它们的干扰素刺激基因的信息却严重缺乏。我们确定了推定的雪貂 IFITM 基因，并绘制了它们完整的基因座。因此，我们的研究填补了知识空白，并支持进一步使用雪貂模型来探索 IFITM 在这些重要疾病中的重要性。
