de Lang Anna, Baas Tracey, Teal Thomas, Leijten Lonneke M, Rain Brandon, Osterhaus Albert D, Haagmans Bart L, Katze Michael G
Department of Virology, Erasmus Medical Center, Rotterdam, The Netherlands.
PLoS Pathog. 2007 Aug 10;3(8):e112. doi: 10.1371/journal.ppat.0030112.
The pathogenesis of severe acute respiratory syndrome coronavirus (SARS-CoV) is likely mediated by disproportional immune responses and the ability of the virus to circumvent innate immunity. Using functional genomics, we analyzed early host responses to SARS-CoV infection in the lungs of adolescent cynomolgus macaques (Macaca fascicularis) that show lung pathology similar to that observed in human adults with SARS. Analysis of gene signatures revealed induction of a strong innate immune response characterized by the stimulation of various cytokine and chemokine genes, including interleukin (IL)-6, IL-8, and IP-10, which corresponds to the host response seen in acute respiratory distress syndrome. As opposed to many in vitro experiments, SARS-CoV induced a wide range of type I interferons (IFNs) and nuclear translocation of phosphorylated signal transducer and activator of transcription 1 in the lungs of macaques. Using immunohistochemistry, we revealed that these antiviral signaling pathways were differentially regulated in distinctive subsets of cells. Our studies emphasize that the induction of early IFN signaling may be critical to confer protection against SARS-CoV infection and highlight the strength of combining functional genomics with immunohistochemistry to further unravel the pathogenesis of SARS.
严重急性呼吸综合征冠状病毒（SARS-CoV）的发病机制可能由不成比例的免疫反应以及该病毒规避天然免疫的能力介导。我们利用功能基因组学分析了青春期食蟹猴（猕猴）肺部对SARS-CoV感染的早期宿主反应，这些食蟹猴表现出与感染SARS的成年人类相似的肺部病理特征。基因特征分析显示，诱导了强烈的天然免疫反应，其特征是刺激多种细胞因子和趋化因子基因，包括白细胞介素（IL）-6、IL-8和IP-10，这与急性呼吸窘迫综合征中观察到的宿主反应一致。与许多体外实验不同，SARS-CoV在食蟹猴肺部诱导了广泛的I型干扰素（IFN）以及磷酸化信号转导子和转录激活子1的核转位。通过免疫组织化学，我们发现这些抗病毒信号通路在不同的细胞亚群中受到差异调节。我们的研究强调，早期IFN信号的诱导可能对抵御SARS-CoV感染至关重要，并突出了将功能基因组学与免疫组织化学相结合以进一步阐明SARS发病机制的优势。
