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.
Highlights
Infection with SARS-CoV causes lower respiratory tract disease with clinical symptoms that include fever, malaise, and lymphopenia [1]
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
A subset of cells was shown to produce interferon-b, a cytokine involved in the resistance to many viral infections and able to activate signal transducer and activator of transcription 1 (STAT1)
Summary
Infection with SARS-CoV causes lower respiratory tract disease with clinical symptoms that include fever, malaise, and lymphopenia [1]. It has been hypothesized that the pathological changes are caused by a disproportional immune response, illustrated by elevated levels of inflammatory cytokines and chemokines, such as CXCL10 (IP-10), CCL2 (MCP-1), interleukin (IL)-6, IL8, IL-12, IL-1b, and interferon (IFN)-c [8,9,10,11,12,13]. These in vivo data have been confirmed with in vitro experiments, demonstrating that SARS-CoV infection induces a range of cytokines and chemokines in diverse cell types [14,15,16,17,18,19]
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