Submitted to: Proceedings of the National Academy of Sciences
Publication Type: Proceedings
Publication Acceptance Date: 2/1/2001
Publication Date: 2/27/2001
Interpretive Summary: In 1918-19, 40 million people died from "flu" or influenza, a virus infection. To determine how this virus caused illness and death, we generated influenza A viruses entirely from DNA through new recombinant molecular technology, called virus rescue. Working in a specially designed safe laboratory, influenza viruses were constructed using one gene, the NS gene, from the 1918 influenza virus and seven genes from a 1933 human influenza virus. This rescued 1918 NS influenza virus grew well in tissue culture, but caused less severe disease in a mouse model than the original 1933 human influenza virus. These results suggest that the NS protein plays a role in development of influenza.
Technical Abstract: The influenza A virus pandemic of 1918-19 killed 40 million people worldwide. We here report the sequence of the A/Brevig Mission/1/18 (H1N1) virus non-structural (NS) segment, encoding two proteins, NS1 and NEP. Phylogenetically, these genes are close to the common ancestor of subsequent human and classical swine strain NS genes. Utilizing the recently developed technique of generating influenza A viruses entirely from cloned cDNAs, the hypothesis that the 1918 virus NS1 gene played a role in virulence was tested in an mouse. Viruses were generated which possessed either the 1918 NS1 gene alone or the entire 1918 NS segment in a background of influenza A/WSN/33 (H1N1), a mouse-adapted virus derived from a human influenza strain first isolated in 1933. These 1918 NS viruses replicated well in tissue culture but were attenuated in mice as compared to the isogenic control viruses. This attenuation in mice may be related to othe human origin of the 1918 NS1 gene. These results suggest that interaction of the NS1 protein with host cell factors plays a significant role in viral pathogenesis.