Lam L K Metthew, Watson Alan M, Ryman Kate D, Klimstra William B
Center for Vaccine Research, Department of Microbiology and Molecular Genetics, University of Pittsburgh, 3501 Fifth Avenue, Pittsburgh, PA 15261 USA.
NPJ Vaccines. 2018 Jan 23;3:5. doi: 10.1038/s41541-017-0039-z. eCollection 2018.
Live attenuated viruses are historically among the most effective viral vaccines. Development of a safe vaccine requires the virus to be less virulent, a phenotype that is historically arrived by empirical evaluation often leaving the mechanisms of attenuation unknown. The yellow fever virus 17D live attenuated vaccine strain has been developed as a delivery vector for heterologous antigens; however, the mechanisms of attenuation remain elusive. The successful and safe progress of 17D as a vaccine vector and the development of live attenuated vaccines (LAVs) to related flaviviruses requires an understanding of the molecular mechanisms leading to attenuation. Using subcutaneous infection of interferon-deficient mouse models of wild type yellow fever virus (WT YFV) pathogenesis and 17D-mediated immunity, we found that, in the absence of type I IFN (IFN-α/β), type II interferon (IFN-γ) restricted 17D replication, but not that of WT YFV, by 1-2 days post-infection. In this context, IFN-γ responses protected 17D-infected animals from mortality, largely restricted the virus to lymphoid organs, and eliminated viscerotropic disease signs such as steatosis in the liver and inflammatory cell infiltration into the spleen. However, WT YFV caused a disseminated infection, gross liver pathology, and rapid death of the animals. In vitro, IFN-γ treatment of myeloid cells suppressed the replication of 17D significantly more than that of WT YFV, suggesting a direct differential effect on 17D virus replication. Together these data indicate that an important mechanism of 17D attenuation in vivo is increased sensitivity to IFN-γ stimulated responses elicited early after infection.
减毒活病毒在历史上一直是最有效的病毒疫苗之一。开发一种安全的疫苗需要使病毒的毒性降低，这种表型在历史上通常是通过经验评估获得的，往往不清楚减毒的机制。黄热病病毒17D减毒活疫苗株已被开发用作异源抗原的递送载体；然而，其减毒机制仍然难以捉摸。17D作为疫苗载体的成功且安全的进展以及相关黄病毒减毒活疫苗（LAV）的开发需要了解导致减毒的分子机制。通过对野生型黄热病病毒（WT YFV）发病机制和17D介导的免疫的干扰素缺陷小鼠模型进行皮下感染，我们发现，在缺乏I型干扰素（IFN-α/β）的情况下，II型干扰素（IFN-γ）在感染后1-2天限制了17D的复制，但不限制WT YFV的复制。在这种情况下，IFN-γ反应保护感染17D的动物免于死亡，在很大程度上限制病毒在淋巴器官中，并消除了诸如肝脏脂肪变性和炎症细胞浸润到脾脏等嗜内脏疾病体征。然而，WT YFV导致了播散性感染、严重的肝脏病理变化以及动物的快速死亡。在体外，用IFN-γ处理髓样细胞对17D复制的抑制作用明显大于对WT YFV的抑制作用，表明对17D病毒复制有直接的差异效应。这些数据共同表明，17D在体内减毒的一个重要机制是对感染后早期引发的IFN-γ刺激反应的敏感性增加。
