Exacerbated innate host response to SARS-CoV in aged non-human primates.
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.
Department of Virology, Erasmus Medical Center, Rotterdam, The Netherlands.
Saskia L
SL
Smits
Anna
A
de Lang
Judith M A
JM
van den Brand
Lonneke M
LM
Leijten
Wilfred F
WF
van IJcken
Marinus J C
MJ
Eijkemans
Geert
G
van Amerongen
Thijs
T
Kuiken
Arno C
AC
Andeweg
Albert D M E
AD
Osterhaus
Bart L
BL
Haagmans
D055371:Acute Lung Injury / Q000276:immunology / Q000821:virology; D000375:Aging / Q000276:immunology*; D000818:Animals; D000893:Anti-Inflammatory Agents / Q000494:pharmacology; D015870:Gene Expression; D020869:Gene Expression Profiling; D007113:Immunity, Innate / Q000276:immunology*; D007150:Immunohistochemistry; D007249:Inflammation / Q000276:immunology; D007370:Interferon Type I / Q000096:biosynthesis / Q000276:immunology / Q000494:pharmacology; D016209:Interleukin-8 / Q000276:immunology; D008251:Macaca; D016328:NF-kappa B / Q000096:biosynthesis / Q000276:immunology; D020411:Oligonucleotide Array Sequence Analysis; D020133:Reverse Transcriptase Polymerase Chain Reaction; D045473:Severe acute respiratory syndrome-related coronavirus / Q000276:immunology; D045169:Severe Acute Respiratory Syndrome / Q000276:immunology*; D015398:Signal Transduction / Q000276:immunology*; D014779:Virus Replication
D000893:Anti-Inflammatory Agents; D007370:Interferon Type I; D016209:Interleukin-8; D016328:NF-kappa B