Genomic analysis of increased host immune and cell death.pdf

Genomic analysis of increased host immune and cell death responses induced by 1918 influenza virus John C. Kash1, Terrence M. Tumpey2, Sean C. Proll3, Victoria Carter3, Olivia Perwitasari1, Matthew J. Thomas3, Christopher F. Basler4, Peter Palese4, Jeffery K. Taubenberger5,?, Adolfo García-Sastre4, David E. Swayne6, and Michael G. Katze1,3 1 Department of Microbiology, University of Washington School of Medicine, Seattle, Washington 98195, USA 2 Influenza Branch, DVRD, NCID, Centers for Disease Control and Prevention, Atlanta, Georgia 30333, USA 3 Washington National Primate Research Center, Seattle, Washington 98195, USA 4 Department of Microbiology, Mount Sinai School of Medicine, New York, New York 10029, USA 5 Department of Molecular Pathology, Department of Cellular Pathology and Genetics, Armed Forces Institute of Pathology, Rockville, Maryland 20850, USA 6 Southeast Poultry Research Laboratory, Agricultural Research Laboratory, US Department of Agriculture, Athens, Georgia 30606, USA Abstract The influenza pandemic of 1918–19 was responsible for about 50 million deaths worldwide1. Modern histopathological analysis of autopsy samples from human influenza cases from 1918 revealed significant damage to the lungs with acute, focal bronchitis and alveolitis associated with massive pulmonary oedema, haemorrhage and rapid destruction of the respiratory epithelium2. The contribution of the host immune response leading to this severe pathology remains largely unknown. Here we show, in a comprehensive analysis of the global host response induced by the 1918 influenza virus, that mice infected with the reconstructed 1918 influenza virus displayed an increased and accelerated activation of host immune response genes associated with severe pulmonary pathology. We found that mice infected with a virus containing all eight genes from the pandemic virus showed marked activation of pro-inflammatory and cell-death pathways by 24 h after infection that remained unabated until d