Paul-Ehrlich-Institut, Langen, Germany.
J Virol. 2011 Apr;85(7):3557-69. doi: 10.1128/JVI.01191-10. Epub 2011 Jan 26.
The emergence of zoonotic orthopoxvirus infections and the threat of possible intentional release of pathogenic orthopoxviruses have stimulated renewed interest in understanding orthopoxvirus infections and the resulting diseases. Ectromelia virus (ECTV), the causative agent of mousepox, offers an excellent model system to study an orthopoxvirus infection in its natural host. Here, we investigated the role of the vaccinia virus ortholog N1L in ECTV infection. Respiratory infection of mice with an N1L deletion mutant virus (ECTVΔN1L) demonstrated profound attenuation of the mutant virus, confirming N1 as an orthopoxvirus virulence factor. Upon analysis of virus dissemination in vivo, we observed a striking deficiency of ECTVΔN1L spreading from the lungs to the livers or spleens of infected mice. Investigating the immunological mechanism controlling ECTVΔN1L infection, we found the attenuated phenotype to be unaltered in mice deficient in Toll-like receptor (TLR) or RIG-I-like RNA helicase (RLH) signaling as well as in those missing the type I interferon receptor or lacking B cells. However, in RAG-1(-/-) mice lacking mature B and T cells, ECTVΔN1L regained virulence, as shown by increasing morbidity and virus spread to the liver and spleen. Moreover, T cell depletion experiments revealed that ECTVΔN1L attenuation was reversed only by removing both CD4(+) and CD8(+) T cells, so the presence of either cell subset was still sufficient to control the infection. Thus, the orthopoxvirus virulence factor N1 may allow efficient ECTV infection in mice by interfering with host T cell function.
人畜共患正痘病毒感染的出现以及潜在的致病正痘病毒蓄意释放的威胁，激发了人们对理解正痘病毒感染及其引发疾病的新兴趣。细弱病毒（ECTV）是引起鼠痘的病原体，为研究自然宿主中的正痘病毒感染提供了极好的模型系统。在这里，我们研究了牛痘病毒同源物 N1L 在 ECTV 感染中的作用。用缺失 N1L 的突变病毒（ECTVΔN1L）对小鼠进行呼吸道感染，证明突变病毒的毒力明显减弱，证实 N1 是正痘病毒的毒力因子。在分析体内病毒传播时，我们观察到 ECTVΔN1L 从肺部向感染小鼠的肝脏或脾脏传播存在明显缺陷。在研究控制 ECTVΔN1L 感染的免疫机制时，我们发现缺失 TLR 或 RIG-I 样 RNA 解旋酶（RLH）信号的小鼠、缺失 I 型干扰素受体或缺乏 B 细胞的小鼠中，这种减毒表型没有改变。然而，在缺乏成熟 B 和 T 细胞的 RAG-1(-/-) 小鼠中，ECTVΔN1L 恢复了毒力，表现为发病率增加和病毒向肝脏和脾脏传播。此外，T 细胞耗竭实验表明，只有去除 CD4(+)和 CD8(+)T 细胞才能逆转 ECTVΔN1L 的衰减，因此，任一细胞亚群的存在仍足以控制感染。因此，正痘病毒毒力因子 N1 可能通过干扰宿主 T 细胞功能，使 ECTV 能够在小鼠中有效感染。
