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The influenza strain responsible for the 1918 pandemic was unusually virulent. In previous studies, investigators gained new insight into this virulence by studying events in mice inoculated with a genetically engineered copy of the strain. Now, a multinational research team has extended this approach to nonhuman primates.
Seven macaques were infected with a re-created 1918 influenza virus and three with a modern H1N1 strain (K173). They were then euthanized 3, 6, or 8 days after infection. High titers of the 1918 virus were detected throughout the respiratory tract; in contrast, K173 was largely limited to the upper airway. Inflammation and lung injury were more pronounced with the 1918 virus. Animals infected with the 1918 virus exhibited greater levels of interleukin (IL)-6 in serum. Host genes modulated by the 1918 virus remained relatively stable throughout infection, whereas the response to K173 changed between early and later stages of the infection. Lung IL-6 mRNA remained elevated at day 8 with the 1918 virus but not with K173. Several key cytokine genes including IL-8 and CXCL11 showed delayed activation with 1918-virus infection. K173-infected animals showed high levels of mRNA for “antiviral” type I interferons. These levels were much lower in 1918-virus–infected animals, despite high viral loads. Two additional genes important in antiviral host response, DDX58 and IFIH1, were increased by K173 but not by the 1918 virus.
Kobasa D et al. Aberrant innate immune response in lethal infection of macaques with the 1918 influenza virus. Nature 2007 Jan 18; 445:319-23.
Comment
These results extend earlier findings in mice to an animal model that should more closely reflect human disease. One or more gene products of the 1918 strain cause unregulated stimulation of tissue-damaging immune responses while preventing responses important in clearing the infection. Additional work is needed to define the mechanisms responsible and to explore the possibility of therapeutically disrupting them.