Immunostimulatory Defective Viral Genomes from Respiratory Syncytial Virus Promote a Strong Innate Antiviral Response during Infection in Mice and Humans

Human respiratory syncytial virus (RSV) is a major cause of severe respiratory illness in children and susceptible adults. RSV blocks the development of the innate antiviral immune response and can grow to high titers in the respiratory tract. Here we demonstrate that immunostimulatory defective viral genomes (iDVGs) that are naturally generated during RSV replication are strong inducers of the innate antiviral response to RSV in mice and humans. In mice, RSV iDVGs stimulated the expression of antiviral genes, restricted viral replication, and prevented weight loss and lung inflammation. In human cells, the antiviral response to RSV iDVGs was dominated by the expression of IFN-λ1 over IFN-β and was driven by rapid intranuclear accumulation of the transcription factor IRF1. RSV iDVGs were detected in respiratory secretions of hospitalized patients, and their amount positively correlated with the level of expression of antiviral genes in the samples. Infection of explanted human lung tissue from different donors revealed that most humans can respond to RSV iDVGs and that the rate of accumulation of iDVGs during infection directly correlates with the quality of the antiviral response. Taken together, our data establish iDVGs as primary triggers of robust antiviral responses to RSV and provide the first evidence for an important biological role for naturally occurring iDVGs during a paramyxovirus infection in humans.

人类呼吸道合胞病毒（Human respiratory syncytial virus, RSV）是引发儿童及易感成年人罹患重症呼吸道疾病的主要病原体。RSV可阻断天然抗病毒免疫应答的发育进程，并能在呼吸道内增殖至较高滴度水平。本研究证实，在RSV复制过程中自然生成的免疫刺激性缺陷病毒基因组（immunostimulatory defective viral genomes, iDVGs），是小鼠与人体内针对RSV的天然抗病毒免疫应答的强效诱导因子。在小鼠模型中，RSV来源的iDVGs可刺激抗病毒基因的表达、限制病毒复制，并预防体重下降与肺部炎症。在人类细胞中，针对RSV的iDVGs介导的抗病毒应答以干扰素λ1（IFN-λ1）的表达相较于干扰素β（IFN-β）占优为核心特征，其驱动机制为转录因子IRF1快速在细胞核内聚集。研究团队在住院患者的呼吸道分泌物中检测到了RSV iDVGs，且其含量与样本中抗病毒基因的表达水平呈正相关。对不同供体来源的移植人体肺组织进行感染实验后发现，绝大多数个体均可对RSV iDVGs产生免疫应答，且感染过程中iDVGs的积累速率与抗病毒应答的质量直接相关。综上，本研究数据证实iDVGs是触发针对RSV的强效抗病毒应答的主要因素，并首次为自然产生的iDVGs在人类副黏病毒（paramyxovirus）感染过程中发挥重要生物学功能提供了实验证据。