Necessity of adaptation of RNA viruses in host switching events between taxonomically distant reservoir animals

RNA病毒在分类学上距离较远的宿主动物之间的宿主转换事件中适应的必要性

• 批准号: 226336799
• 负责人: Professor Dr. Marcel Müller
• 金额: --
• 依托单位: Institut für Virologie (CCM)
• 依托单位国家: 德国
• 项目类别: Priority Programmes
• 财政年份: 2013
• 资助国家: 德国
• 起止时间: 2012-12-31 至 2015-12-31
• 项目状态: 已结题
• 来源: https://gepris.dfg.de/gepris/projekt/226336799?language=en
• 关键词: Necessity; adaptation; RNA; viruses; host

The majority of emerging infectious diseases are caused by zoonotic RNA viruses often transmitted by bats, rodents and birds. Their high mutation rate allows fast adaptation to novel species increasing the risk for zoonotic host transitions. Host defense mechanisms like the innate immune response are conserved among higher vertebrates and represent a major obstacle that viruses have to overcome. The interferon (IFN) system as part of the innate immune response is among the first and most effective antiviral defense mechanisms and viruses have evolved efficient countermeasures (IFN antagonists) to inhibit the induction and signaling of IFN. It can thus be assumed that the IFN system is fate-determining for viral host switching events.The aim of the proposed project is to analyze if the necessity for viruses to adapt during host transition correlates on a quantitative scale with the phylogenetic distance between hosts of interest. We will focus our study on the ability of viruses to antagonize the species-specific IFN induction pathway of different hosts. To this end we want to quantify the activity of known viral anti- IFN proteins of six selected viruses (SARS-Coronavirus, Ebola-, Nipah-, Rabies-, Hanta- and Influenza A virus) in cell cultures from 12 different mammalian/avian species. This will be done by overexpressing the antagonists in the respective cell cultures followed by stimulation of the IFN induction. Cell cultures from the predicted natural hosts will be used as reference. The IFN mRNA expression will be measured by species-specific real-time RT-PCRs. The IFN secretion will be determined by an established calibrated pan-species vesicular stomatitis virus-based bioassay. Quantitative outcomes of the in-vitro IFN experiments will be directly correlated with inter-host patristic distances based on different gene clusters. The latter shall be expressed along single and concatenated gene trees calculated by ML- and Bayesian methods. Since we are interested in innate immune responses we will also include genes and promoters specifically involved in the IFN response.As a long-term goal we want to identify virus family- or inter-host distance-specific patterns that will facilitate risk assessment of novel reservoir-borne viruses immediately as they are being detected.

大多数新出现的传染病是由人畜共患RNA病毒引起的，通常由蝙蝠、啮齿动物和鸟类传播。它们的高突变率允许快速适应新物种，增加了人畜共患病宿主转换的风险。宿主防御机制，如先天免疫反应，在高等脊椎动物中是保守的，是病毒必须克服的主要障碍。干扰素（IFN）系统作为先天免疫应答的一部分是最早和最有效的抗病毒防御机制之一，并且病毒已经进化出有效的对抗措施（IFN拮抗剂）来抑制IFN的诱导和信号传导。因此，可以假设，IFN系统是决定命运的病毒宿主转换events.The拟议项目的目的是分析，如果病毒的必要性，以适应在主机转换相关的定量尺度与感兴趣的主机之间的系统发育距离。我们将集中研究病毒拮抗不同宿主的种特异性IFN诱导途径的能力。为此，我们想要定量来自12种不同哺乳动物/禽类物种的细胞培养物中6种选定病毒（SARS-冠状病毒、埃博拉病毒、尼帕病毒、狂犬病病毒、汉他病毒和甲型流感病毒）的已知病毒抗IFN蛋白的活性。这将通过在各自的细胞培养物中过表达拮抗剂，然后刺激IFN诱导来完成。来自预测天然宿主的细胞培养物将用作参考。将通过种特异性实时RT-PCR测量IFN mRNA表达。将通过已建立的基于校准泛种属水泡性口炎病毒的生物测定法测定IFN分泌。体外IFN实验的定量结果将与基于不同基因簇的宿主间父系距离直接相关。后者应沿着通过ML和贝叶斯方法计算的单个和级联基因树表达沿着。由于我们对先天免疫应答感兴趣，我们也将包括IFN应答中特异性参与的基因和启动子。作为一个长期目标，我们希望确定病毒家族或宿主间距离特异性模式，这将有助于在检测到新的病毒传播病毒时立即进行风险评估。