FAS - 1918 Influenza Case Study

Federation of American Scientists Case Studies in Dual Use Biological Research Module 5.0: Antibiotic Resistance Case Study

Using Taubenbergers sequence, Basler and coworkers were able to generate a virus that contained all eight of the viral gene segments from the 1918 influenza virus. Since the non-coding regions of the 1918 virus have not been sequenced, those regions from a related H1N1 influenza virus were used for the reconstruction. Two different H1N1 variants currently found in humans were used as a control. In another set of controls, the researchers generated hybrid viruses that had some genes from one current H1N1 variant (called Tx/91) and some from the 1918 variant. These swapping experiments generated several viruses with different combinations of viral gene segments from both the contemporary Tx/91 and 1918 influenza virus.

Cleavage of the HA molecule is required for the influenza virus to enter the host cell and replicate and can be accomplished by the addition of trypsin to infected cells. However, some variants of influenza are able to replicate without addition of trypsin, and this ability is generally an indicator of greater pathogenicity. The complete 1918 virus, the

hybrid Tx/91 virus carrying the 1918 HA and NA genes, and the hybrid Tx/91virus carrying only the 1918 NA gene were able to replicate without trypsin added. This suggests that the 1918 NA is able to facilitate HA cleavage, therefore offering a possible explanation for its high pathogenicity.

In order to directly compare the pathogenicty of the 1918 influenza virus with the contemporary Tx/91 H1N1 virus, mice were infected and had their weight and lung virus titers monitored. Just four days after infection, mice with 1918 influenza had 39,000 times the number of virus particles in their lungs than mice infected with the Tx/91 control strain. In addition, the control mice lost some weight in the first few days of infection, but all survived and had regained the weight by the end of the fourteen day study. Mice infected with the1918 strain, however, very rapidly lost weight and had all died within five days. Baslers team also looked at the lung tissue and other organs of infected mice to determine the type and extent of disease. Just as described in autopsy reports from victims of the Spanish flu pandemic, there was severe disease in the lungs, but not in the spleen or other organs.