Lung epithelial cells have virus-specific and shared gene expression responses to infection by diverse respiratory viruses

The severity of respiratory viral infections is partially determined by the cellular response mounted by infected lung epithelial cells. Disease prevention and treatment is dependent on our understanding of the shared and unique responses elicited by diverse viruses, yet few studies compare host responses to viruses from different families while controlling other experimental parameters. Murine models are commonly used to study the pathogenesis of respiratory viral infections, and in vitro studies using murine cells provide mechanistic insight into the pathogenesis observed in vivo. We used microarray analysis to compare changes in gene expression of murine lung epithelial cells infected individually by three respiratory viruses causing mild (rhinovirus, RV1B), moderate (coronavirus, MHV-1), and severe (influenza A virus, PR8) disease in mice. RV1B infection caused numerous gene expression changes, but the differential effect peaked at 12 hours post-infection. PR8 altered an intermediate number of genes whose expression continued to change through 24 hours. MHV-1 had comparatively few effects on host gene expression. The viruses elicited highly overlapping responses in antiviral genes, though MHV-1 induced a lower type I interferon response than the other two viruses. Signature genes were identified for each virus and included host defense genes for PR8, tissue remodeling genes for RV1B, and transcription factors for MHV-1. Our comparative approach identified universal and specific transcriptional signatures of virus infection that can be used to distinguish shared and virus-specific mechanisms of pathogenesis in the respiratory tract.

呼吸道病毒感染的严重程度，部分由受感染肺上皮细胞（lung epithelial cells）所触发的细胞应答所决定。疾病的防控依赖于我们对不同病毒所引发的共有与独有应答的理解，但目前鲜有研究在控制其他实验参数（experimental parameters）的前提下，比较宿主对不同科属病毒的应答差异。小鼠模型（murine models）常被用于研究呼吸道病毒感染的发病机制，而利用小鼠细胞开展的体外（in vitro）研究则可为体内（in vivo）观察到的发病机制提供机制层面的解析。本研究通过基因芯片分析（microarray analysis），比较了三种分别可在小鼠体内引发轻度（鼻病毒RV1B，rhinovirus RV1B）、中度（冠状病毒MHV-1，coronavirus MHV-1）及重度（甲型流感病毒PR8，influenza A virus PR8）疾病的呼吸道病毒，对小鼠肺上皮细胞基因表达的影响。RV1B感染可引发大量基因表达变化，但其差异表达效应在感染后12小时达到峰值；PR8可改变中等数量基因的表达，且这些基因的表达变化可持续至感染后24小时；而MHV-1对宿主基因表达的影响相对较少。尽管三种病毒均可诱导高度重叠的抗病毒基因应答，但MHV-1所诱导的I型干扰素（type I interferon）应答水平低于另外两种病毒。本研究分别鉴定出了每种病毒对应的特征基因（signature genes），其中包括PR8对应的宿主防御基因、RV1B对应的组织重塑基因以及MHV-1对应的转录因子（transcription factors）。本研究通过比较分析，鉴定出了病毒感染的通用与特异性转录特征（transcriptional signatures），可用于区分呼吸道（respiratory tract）感染中病毒相关的共有致病机制与病毒特异性致病机制。