Lethal Influenza Virus Infection in Macaques Is Associated with Early Dysregulation of Inflammatory Related Genes

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Abstract
The enormous toll on human life during the 1918–1919 Spanish influenza pandemic is a constant reminder of the potential lethality of influenza viruses. With the declaration by the World Health Organization of a new H1N1 influenza virus pandemic, and with continued human cases of highly pathogenic H5N1 avian influenza virus infection, a better understanding of the host response to highly pathogenic influenza viruses is essential. To this end, we compared pathology and global gene expression profiles in bronchial tissue from macaques infected with either the reconstructed 1918 pandemic virus or the highly pathogenic avian H5N1 virus A/Vietnam/1203/04. Severe pathology was observed in respiratory tissues from 1918 virus-infected animals as early as 12 hours after infection, and pathology steadily increased at later time points. Although tissues from animals infected with A/Vietnam/1203/04 also showed clear signs of pathology early on, less pathology was observed at later time points, and there was evidence of tissue repair. Global transcriptional profiles revealed that specific groups of genes associated with inflammation and cell death were up-regulated in bronchial tissues from animals infected with the 1918 virus but down-regulated in animals infected with A/Vietnam/1203/04. Importantly, the 1918 virus up-regulated key components of the inflammasome, NLRP3 and IL-1β, whereas these genes were down-regulated by A/Vietnam/1203/04 early after infection. TUNEL assays revealed that both viruses elicited an apoptotic response in lungs and bronchi, although the response occurred earlier during 1918 virus infection. Our findings suggest that the severity of disease in 1918 virus-infected macaques is a consequence of the early up-regulation of cell death and inflammatory related genes, in which additive or synergistic effects likely dictate the severity of tissue damage. The world is currently experiencing a pandemic caused by a new type of H1N1 influenza virus that originated in swine. Although it is too early to tell how virulent this new virus may be, some influenza viruses can cause severe disease. The 1918 pandemic, also caused by an H1N1 virus, resulted in over 50 million deaths worldwide. Highly pathogenic avian H5N1 influenza viruses are circulating in several parts of the world, and although human infection has been rare, the virus often causes a lethal illness. To determine whether highly pathogenic influenza viruses cause disease by similar means, we used a macaque infection model to study the host response to the reconstructed 1918 virus and an avian H5N1 isolate known as VN/1203. We found that although both viruses caused severe disease, infection with the 1918 virus was more likely to result in death, whereas animals infected with VN/1203 recovered from infection. In animals infected with the 1918 virus, there was increased expression of genes associated with inflammation, and these genes were turned on as early as 12 hours after infection. Drugs that limit the early inflammatory response may therefore be of benefit in treating infections caused by highly pathogenic influenza viruses.