Interaction of the SARS-Coronavirus with the interferon system

α/β干扰素(IFN)是一种具有抗病毒活性的细胞因子。它们由病毒感染诱导，并触发抗病毒蛋白的表达。为了抵消这一点，病毒进化出了所谓的干扰素拮抗剂，它可以干扰干扰素的诱导、干扰素信号传递或干扰素效应蛋白的作用。我们发现，SARS冠状病毒可被干扰素-β和一种新型干扰素--干扰素-omega强烈抑制。相比之下，干扰素-α的效果较差。此外，还发现感染SARS-CoV的细胞不能合成干扰素，这表明SARS-CoV至少编码了一个具有干扰素拮抗活性的因子。德国团队的拟议研究将旨在：(I)确定宿主编码的干扰素诱导蛋白，这些蛋白负责抗SARS-CoV的抗病毒作用；(Ii)筛选SARS-CoV基因组中具有抗干扰素活性的蛋白；以及(Iii)表征干扰素拮抗机制。中国团队将调查来自中国患者的病毒分离株，以寻找抗干扰素基因的潜在差异。中国病毒分离株的干扰素拮抗基因的活性将相互比较，并与细胞培养适应的病毒分离株进行比较。此外，不同的干扰素水平将在患者的材料中进行测量，并测试是否与疾病进展和某些干扰素拮抗剂序列有关。干扰素-omega是中国FDA批准的通过鼻腔喷雾预防SARS的药物。关于干扰素-omega、-β或-α-in的抗病毒作用和不同诱导的干扰素效应的比较研究将有助于阐明哪种抗病毒蛋白最有效地抑制SARS-CoV。这些研究可能有助于确定影响SARS冠状病毒感染结局的毒力机制和宿主防御因素。这些研究的长期好处可能是改善抗病毒治疗和合理设计SARS冠状病毒疫苗。

Alpha/beta interferons (IFNs) are potent cytokines with antiviral activity. They are induced by virus infection and trigger the expression of antiviral proteins. To counteract this, viruses have evolved so-called IFN antagonists, which interfere with either IFN induction, IFN signaling, or the action of IFN effector proteins. We found that SARS-CoV is strongly inhibited by IFN-beta and by a novel IFN, IFN-omega. IFN-alpha, by contrast, was less effective. Furthermore, it was found that cells infected with SARS-CoV are unable to synthesize IFN, indicating that SARS-CoV encodes at least one factor with IFN-antagonistic activity. The proposed studies of the German team will be aimed at (i) identifying the host-encoded IFN-induced proteins which are responsible for the antiviral effect against SARS-CoV, (ii) screening the SARS-CoV genome for proteins with anti-IFN activity, and (iii) characterizing the IFN-antagonistic mechanism. The Chinese team will investigate virus isolates from Chinese patients for potential differences in the anti-IFN genes. The activity of those IFN-antagonistic genes of Chinese virus isolates will be compared to each other and to cell culture adapted virus isolates. Furthermore, levels of different IFNs will be measured in patients' material and tested whether there is a correlation with disease progression and with certain IFN antagonist sequences. IFN-omega is licensed by the Chinese FDA for prevention of SARS by intranasal spray application. Comparative studies concerning the antiviral effects and the differently induced IFN effectors of IFN-omega, -beta, or -alpha in will help to clarify which antiviral protein most potently inhibits SARS-CoV. These studies may lead to the identification of virulence mechanisms and host defense factors which influence the outcome of infection with SARS-CoV. Long-term benefits of those studies could be the improvement of antiviral therapy and the rational design of SARS-CoV vaccines.