THE GLOBAL HOST IMMUNE RESPONSE: CONTRIBUTION OF HA AND NA GENES FROM THE 1918 SPANISH INFLUENZA TO VIRAL PATHOGENESIS

Authors: KASH, JOHN - UNIV OF WA-SEATTLE, WA; BASLER, CHRISTOPHER - MT SINAI-NEW YORK,NY; GARCIA-SASTRE, ADOLFO - MT SINAI-NEW YORK, NY; CARTER, VICTOR - UNIV OF WA-SEATTLE, WA; BILLHARZ, ROSALIND - UNIV OF WA-SEATTLE, WA; Swayne, David; PRZYGODSKI, RONALD - ARMED FORCES INST-WASH,DC; TAUBENBERGER, JEFFERY - ARMED FORCES INST-WASH, D; PALESE, PETER - MT SINAI-NEW YORK,NY; KATZE, MICHAEL - UNIV OF WA-SEATTLE, WA; Tumpey, Terrence

Submitted to: Journal of Virology
Publication Type: Peer Reviewed Journal
Publication Acceptance Date: 4/21/2004
Publication Date: 9/1/2004
Citation: Kash, J.C., Basler, C.F., Garcia-Sastre, A., Carter, V., Billharz, R., Swayne, D.E., Przygodski, R.M., Taubenberger, J.K., Palese, P., Katze, M.G., Tumpey, T. 2004. The global host immune response: Contribution of HA and NA genes from the 1918 Spanish influenza to viral pathogenesis. Journal of Virology. 78(17):9499-9511.

Interpretive Summary: The 1918 Spanish flu was a devastating disease for humans. To understand how the virus caused disease, we studied the effect of two genes, the hemagglutinin and neuraminidase, on production of disease in a mouse model system. The influenza virus containing the 1918 flu genes killed mice by causing severe damage to the lungs. There was activation in the mice many genes that direct the inflammatory process especially genes that activated T-lymphocytes and macrophages and damaged the lung.

Technical Abstract: To better understand the high virulence associated with the 1918 pandemic influenza virus, we have studied the effects of the A/Brevig Mission/1/18 HA and NA genes during infection in mice under biosafety level 3 (agricultural) conditions. Using histopathology and cDNA microarrays, we examined the consequences of expression of the 1918 HA and NA genes in a recombinant influenza A/WSN/33 virus compared to parental A/WSN/33 virus and to a control virus expressing the HA and NA genes from the recent human isolate, A/New Caledonia/20/99. The 1918 HA/NA:WSN and WSN recombinant viruses were highly lethal for mice and displayed severe lung pathology in comparison to the non-lethal New Caledonia HA/NA:WSN recombinant virus. Expression microarray analysis performed on lung tissues isolated from the infected animals showed activation of many genes involved in the inflammatory response, including cytokine, apoptosis, and lymphocyte genes that were common to all three infection groups. However, consistent with the histopathology studies, the WSN and 1918 HA/NA:WSN recombinant viruses showed up-regulated levels of genes expressed in activated T cells and macrophages, as well as genes involved in apoptosis, tissue injury and oxidative damage that were not observed in the New Caledonia HA/NA:WSN recombinant virus infected mice. These studies suggest a putative role for the HA and NA genes in the high virulence and mortality associated with the pandemic influenza of 1918.