Journal Article

Aberrant innate immune response in lethal infection of macaques with the 1918 influenza virus

Alimonti, Judie B., Feldmann, Heinz, Ebihara, Hideki, Feldmann, Friederike, Copps, John, Fernando, Lisa, Hatta, Yasuko, Kash, John C., Kobasa, Darwyn, Kawaoka, Yoshihiro, Hatta, Masato, Hyun Kim, Jin, Li, Yan, Jones, Steven M., Shinya, Kyoko, Halfmann, Peter, Katze, Michael G.

2007

Overview

The deadly 1918 flu virus The 1918 'Spanish flu' influenza pandemic was unusually severe, causing about 50 million deaths. Why was it so destructive? The lack of antibiotics to fight secondary infections, and socioeconomic factors may be relevant. But experimental infection of nonhuman primates with reconstructed 1918 virus suggests that the lethal nature of the virus itself was a big factor. It is in fact the only influenza virus lethal to experimentally infected nonhuman primates, and the 1918 virus, unlike other strains, suppresses innate immune responses. The H5N1 viruses now circulating cause a severe lung infection similar to that caused by the 1918 virus and also suppress innate immunity, so therapies that protect this type of host immunity might reduce the severity of infection due to these influenza viruses. The 1918 influenza pandemic was unusually severe, resulting in about 50 million deaths worldwide 1 . The 1918 virus is also highly pathogenic in mice, and studies have identified a multigenic origin of this virulent phenotype in mice 2 , 3 , 4 . However, these initial characterizations of the 1918 virus did not address the question of its pathogenic potential in primates. Here we demonstrate that the 1918 virus caused a highly pathogenic respiratory infection in a cynomolgus macaque model that culminated in acute respiratory distress and a fatal outcome. Furthermore, infected animals mounted an immune response, characterized by dysregulation of the antiviral response, that was insufficient for protection, indicating that atypical host innate immune responses may contribute to lethality. The ability of influenza viruses to modulate host immune responses, such as that demonstrated for the avian H5N1 influenza viruses 5 , may be a feature shared by the virulent influenza viruses.

• Publisher: Nature Publishing Group UK,Nature Publishing,Nature Publishing Group
• Subject: Animals / Biological and medical sciences / Chemokines - blood / Cynomolgus / Cytokines - blood / Disease Models, Animal / Female / Fundamental and applied biological sciences. Psychology / Gene Expression Profiling / Gene Expression Regulation / Genotype & phenotype / Health aspects / Human viral diseases / Humanities and Social Sciences / Humans / Immune response / Immunity, Innate - immunology / Immunology / Infections / Infectious diseases / Influenza / Influenza A Virus, H1N1 Subtype - genetics / Influenza A Virus, H1N1 Subtype - immunology / Influenza A Virus, H1N1 Subtype - pathogenicity / Influenza virus / Influenza viruses / Influenza, Human - blood / Influenza, Human - immunology / Influenza, Human - virology / letter / Lung - metabolism / Lung - pathology / Lung - virology / Macaca / Macaca fascicularis - immunology / Macaca fascicularis - virology / Macaques / Medical sciences / Mice / Mice, Inbred BALB C / Microbiology / multidisciplinary / Observations / Oligonucleotide Array Sequence Analysis / Pandemics / Primates / Replicative cycle, interference, host-virus relations, pathogenicity, miscellaneous strains / Science / Science (multidisciplinary) / Survival Rate / Time Factors / Viral diseases / Viral diseases of the respiratory system and ent viral diseases / Virology / Virus Replication