Institute of Virology and Immunobiology, Julius Maximilian University, Versbacher Strasse 7, D-97078 Würzburg, Germany.
J Virol. 2011 May;85(9):4071-84. doi: 10.1128/JVI.01365-10. Epub 2011 Feb 9.
Infection of mice with pneumonia virus of mice (PVM) provides a convenient experimental pathogenesis model in a natural host for a human respiratory syncytial virus-related virus. Extending our previous work showing that the PVM nonstructural (NS) proteins were pathogenicity factors in mice, we identify both the NS1 and NS2 proteins as antagonists of alpha/beta interferon (IFN-α/β) and IFN-λ by use of recombinant PVM (rPVM) with single and combined deletions of the NS proteins (ΔNS1, ΔNS2, and ΔNS1 ΔNS2). Wild-type and NS deletion PVMs were evaluated for growth and pathogenesis by infecting knockout mice that lack functional receptors to IFN-α/β, IFN-λ, or both. The absence of the receptor to IFN-α/β (IFNAR) or IFN-λ (interleukin-28 receptor α chain [IL-28Rα]) individually did not reverse the attenuated virulence of the NS deletion viruses although loss of IFNAR partially restored replication efficiency. When both receptors were deleted, replication and virulence were largely rescued for rPVM ΔNS1 and were significantly but not completely rescued for rPVM ΔNS2. As for rPVM ΔNS1 ΔNS2, the effect was mostly limited to partial enhancement of replication. This indicates that both IFN-α/β and IFN-λ contributed to restricting the NS deletion viruses, with the former playing the greater role. Interestingly, the replication and virulence of wild-type PVM were completely unaffected by the presence or absence of functional receptors to IFN-α/β and IFN-λ, indicating that both systems are strongly suppressed during infection. However, pretreatment of mice with IFN-α/β was protective against lethal rPVM challenge, whereas pretreatment with IFN-λ delayed but did not prevent disease and, in some cases, reduced mortality. The fact that virulence of rPVM lacking NS2 was not recovered completely when both interferon receptors were deleted suggests that NS2 may have further functions outside the IFN system.
用感染肺炎病毒（PVM）的小鼠建立的实验性发病机制模型，为研究与人呼吸道合胞病毒相关的病毒在天然宿主中的发病机制提供了便利。在我们之前的研究中发现，PVM 的非结构（NS）蛋白是小鼠中的致病性因素，我们通过使用单个和组合缺失 NS 蛋白（ΔNS1、ΔNS2 和 ΔNS1 ΔNS2）的重组 PVM（rPVM），鉴定出 NS1 和 NS2 蛋白均为 α/β 干扰素（IFN-α/β）和 IFN-λ 的拮抗剂。通过感染缺乏 IFN-α/β、IFN-λ 或两者功能受体的基因敲除小鼠，评估野生型和 NS 缺失 PVM 的生长和发病情况。尽管缺失 IFNAR 部分恢复了复制效率，但 IFN-α/β（IFNAR）或 IFN-λ（白细胞介素 28 受体 α 链 [IL-28Rα]）受体的缺失并没有逆转 NS 缺失病毒的毒力减弱。当两种受体都缺失时，rPVM ΔNS1 的复制和毒力得到了很大程度的恢复，而 rPVM ΔNS2 的复制和毒力则得到了显著但不完全的恢复。对于 rPVM ΔNS1 ΔNS2，这种作用主要局限于复制的部分增强。这表明 IFN-α/β 和 IFN-λ 均有助于限制 NS 缺失病毒，前者发挥更大的作用。有趣的是，野生型 PVM 的复制和毒力不受 IFN-α/β 和 IFN-λ 功能受体的存在或缺失的影响，表明这两种系统在感染过程中均受到强烈抑制。然而，用 IFN-α/β 预处理可预防致死性 rPVM 攻击，而用 IFN-λ 预处理可延迟但不能预防疾病，在某些情况下还可降低死亡率。当两种干扰素受体缺失时，rPVM 缺失 NS2 的毒力并未完全恢复，这表明 NS2 可能在 IFN 系统之外具有其他功能。
