Functional Genomics Highlights Differential Induction of Antiviral Pathways in the Lungs of SARS-CoV–Infected Macaques

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Abstract
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. Severe acute respiratory syndrome coronavirus (SARS-CoV) infection causes a progressive atypical pneumonia. In typical cases, largely confined to adult and elderly individuals, acute respiratory distress syndrome develops, and admission to an intensive care unit is required. Although these complications can be fatal, most SARS patients recover, suggesting that protective immune responses are operational. In this study, we simultaneously examined virus replication and host–response gene expression profiles in macaque lungs during the acute phase of SARS to gain more insight into the early events that take place after SARS-CoV infection. We show that a strong host response is induced in the lungs of SARS-CoV–infected macaques, illustrated by the induction of several pathogenic cytokines and chemokines. Interestingly, antiviral pathways are activated as well, demonstrated by the presence of phosphorylated signal transducer and activator of transcription 1 (STAT1) transcription factors throughout the lung, but not in SARS-CoV–infected cells. A subset of cells was shown to produce interferon-β, a cytokine involved in the resistance to many viral infections and able to activate STAT1. Activation of this antiviral pathway upon SARS-CoV infection may be an important escape route of the host to withstand the devastating effects of SARS-CoV.