Our manuscript is one of several recent studies that have helped to provide an understanding of why the 1918 pandemic was so severe and perhaps also why young adults, normally not found susceptible to serious disease from influenza infection, were the hardest hit age group during the pandemic.

“In the course of an infection with a typical influenza virus, like those responsible for influenza cases each year, the immune system of an infected person is well-equipped to handle the virus.”

With the current awareness of the possibility of a new, potentially severe, pandemic caused by the highly pathogenic avian H5N1 influenza virus or bird flu, there is considerable interest in how very virulent viruses cause disease. The 1918 virus, itself a bird virus that crossed into humans, is an important model virus for understanding what we might expect from a pandemic caused by the H5N1 virus and how this threat can be managed.

The study brings together a number of new developments in the influenza virus research field that were needed for this project. These include the remarkable effort to determine the sequences of all the viral genes from the preserved tissues of victims of the 1918 pandemic, and the reverse genetics methods which were used to reconstruct the live virus from synthetic copies of the genes. The 1918 virus was an extinct organism and only now are enough information and techniques available for use in order to resurrect the virus.

In the course of an infection with a typical influenza virus, like those responsible for influenza cases each year, the immune system of an infected person is well-equipped to handle the virus. There are many components of the immune system that all work together to suppress the spread of a virus, block it from reproducing copies of itself and eventually repel the virus entirely from the body. It is clear from work done by all groups studying the 1918 virus that this virus is unusually well-adapted in replicating rapidly to very high levels and this is quite an important aspect of its ability to cause severe disease.

Furthermore, our research in macaques has shown that when their immune system responds to the virus, it over-reacts, and such a strong response is triggered that it actually increases the destruction of lung tissue. It is likely that this excessive response is triggered, at least in part, by the very rapid and extensive growth of the virus, but it is also possible that the virus has specific ways of interfering with the immune response that block normal responses which regulate the immune response.

Our lab specializes in influenza virus research and we had a great interest in studying the 1918 virus as soon as the sequences were made available. Although some of the procedures to reconstruct the virus were time-consuming and somewhat technically challenging, no particularly substantial obstacles were encountered.

Now that we have a good idea of the larger picture of events which lead to the development of severe disease in infected animals, we would like to better understand the precise mechanisms that are used by the virus to cause disease. We shall design experiments that will show us how each of the viral components contributes to disease and, in turn, how an infected animal responds to these viral properties.

Probably, the most important social implication is that research into viruses that caused previous pandemics will help us to prepare for future pandemics. By understanding these viruses better and how they cause disease, we can better prepare for the use of antiviral drugs and support strategies in order to lessen the impact of future pandemics. We can identify new targets for drug design and optimize vaccines and treatment methods, while using the 1918 virus as a model system.

Darwyn Kobasa, Ph.D.
Special Pathogens Program National Microbiology Laboratory
Public Health Agency of Canada
Winnipeg, Manitoba, Canada

Yoshihiro Kawaoka, DVM, Ph.D.
Professor and Director
International Research Center for Infectious Diseases and Division of Virology
Department of Microbiology and Immunology Institute of Medical Science
University of Tokyo
Tokyo, Japan
And
Professor
Department of Pathobiological Sciences
School of Veterinary Medicine
University of Wisconsin-Madison
Madison, WI, USA