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

PLoS Pathog. 2007 Aug 10;3(8):e112. doi: 10.1371/journal.ppat.0030112.

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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Biomarkers / metabolism
  • Cytokines / genetics
  • Cytokines / metabolism
  • Disease Models, Animal
  • Gene Expression Profiling
  • Gene Expression Regulation, Viral*
  • Genomics*
  • Immunohistochemistry
  • Interferon Type I / biosynthesis
  • Interferon Type I / genetics
  • Lung / immunology
  • Lung / pathology
  • Lung / virology*
  • Macaca fascicularis*
  • Oligonucleotide Array Sequence Analysis
  • SARS Virus / genetics*
  • SARS Virus / pathogenicity
  • STAT1 Transcription Factor / metabolism
  • Severe Acute Respiratory Syndrome / metabolism
  • Severe Acute Respiratory Syndrome / pathology
  • Severe Acute Respiratory Syndrome / virology*
  • Virus Replication

Substances

  • Biomarkers
  • Cytokines
  • Interferon Type I
  • STAT1 Transcription Factor