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

Saskia L. Smits, Anna de Lang, Judith M A van den Brand, Lonneke M Leijten, Wilfred F J van IJcken, Marinus J C Eijkemans, Geert van Amerongen, Thijs Kuiken, Arno C Andeweg, Albert D M E Osterhaus, Bart L Haagmans

Research output: Contribution to journalArticleAcademicpeer-review

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.

Original languageEnglish
Pages (from-to)e1000756
JournalPLoS Pathogens
Volume6
Issue number2
DOIs
Publication statusPublished - 5 Feb 2010

Keywords

  • Acute Lung Injury
  • Aging
  • Animals
  • Anti-Inflammatory Agents
  • Gene Expression
  • Gene Expression Profiling
  • Immunity, Innate
  • Immunohistochemistry
  • Inflammation
  • Interferon Type I
  • Interleukin-8
  • Macaca
  • NF-kappa B
  • Oligonucleotide Array Sequence Analysis
  • Reverse Transcriptase Polymerase Chain Reaction
  • SARS Virus
  • Severe Acute Respiratory Syndrome
  • Signal Transduction
  • Virus Replication
  • Journal Article
  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

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