Exacerbated innate host response to SARS-CoV in aged non-human primates

PLoS Pathog. 2010 Feb 5;6(2):e1000756. doi: 10.1371/journal.ppat.1000756.

Abstract

The emergence of viral respiratory pathogens with pandemic potential, such as severe acute respiratory syndrome coronavirus (SARS-CoV) and influenza A H5N1, urges the need for deciphering their pathogenesis to develop new intervention strategies. SARS-CoV infection causes acute lung injury (ALI) that may develop into life-threatening acute respiratory distress syndrome (ARDS) with advanced age correlating positively with adverse disease outcome. The molecular pathways, however, that cause virus-induced ALI/ARDS in aged individuals are ill-defined. Here, we show that SARS-CoV-infected aged macaques develop more severe pathology than young adult animals, even though viral replication levels are similar. Comprehensive genomic analyses indicate that aged macaques have a stronger host response to virus infection than young adult macaques, with an increase in differential expression of genes associated with inflammation, with NF-kappaB as central player, whereas expression of type I interferon (IFN)-beta is reduced. Therapeutic treatment of SARS-CoV-infected aged macaques with type I IFN reduces pathology and diminishes pro-inflammatory gene expression, including interleukin-8 (IL-8) levels, without affecting virus replication in the lungs. Thus, ALI in SARS-CoV-infected aged macaques developed as a result of an exacerbated innate host response. The anti-inflammatory action of type I IFN reveals a potential intervention strategy for virus-induced ALI.

Publication types

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

MeSH terms

  • Acute Lung Injury / immunology
  • Acute Lung Injury / virology
  • Aging / immunology*
  • Animals
  • Anti-Inflammatory Agents / pharmacology
  • Gene Expression
  • Gene Expression Profiling
  • Immunity, Innate / immunology*
  • Immunohistochemistry
  • Inflammation / immunology
  • Interferon Type I / biosynthesis
  • Interferon Type I / immunology
  • Interferon Type I / pharmacology
  • Interleukin-8 / immunology
  • Macaca
  • NF-kappa B / biosynthesis
  • NF-kappa B / immunology
  • Oligonucleotide Array Sequence Analysis
  • Reverse Transcriptase Polymerase Chain Reaction
  • SARS Virus / immunology
  • Severe Acute Respiratory Syndrome / immunology*
  • Signal Transduction / immunology*
  • Virus Replication

Substances

  • Anti-Inflammatory Agents
  • Interferon Type I
  • Interleukin-8
  • NF-kappa B