The 1918 Spanish influenza was one of the deadliest pandemics in human history, and researchers still don’t know why that particular strain was such an effective killer. A new study suggests that flu patients’ immune systems played a surprising role. Rather than striking out against just the flu virus, victims’ immune systems may have launched furious attacks that devastated their lungs.
Since removing virus samples from the body of a 1918 flu victim that was excavated from permafrost in 1997, researchers have searched for unique characteristics that made the bug so deadly. Last year, a team led by Jeffery Taubenberger of the Armed Forces Institute of Pathology in Rockville, Md., finished sequencing the virus’ eight unique genes and reconstructed the original killer (SN: 10/8/05, p. 227: Killer Findings: Scientists piece together 1918-flu virus).
Researchers have examined that reconstruction, as well as individual genes from this virus, to determine how the 1918 strain infected cells. However, notes microbiologist Michael G. Katze of the University of Washington in Seattle, scientists hadn’t learned much about how an infected person’s immune system reacted once the virus had settled in.
To model that reaction, Katze and his colleagues infected groups of mice with one of four viruses: the reconstructed 1918 flu strain, either of two strains constructed to carry subsets of the 1918 flu’s genes, or a contemporary flu strain. The researchers collected lung tissue from the animals as their infections progressed.
The team saw a quick and massive influx of immune cells, such as neutrophils and macrophages, in lung tissue from mice infected with the reconstructed 1918 strain. These lung samples were also extremely inflamed and riddled with dead cells. Lungs of mice infected with viruses carrying 1918 gene subsets had far fewer immune cells in the lungs and less inflammation and cell death. Lungs from animals infected with the contemporary flu strain showed few, if any, of these effects.
The scientists also compared gene activity among lung samples from the four groups of mice. Genes responsible for launching an immune attack, turning on inflammation, and triggering cell suicide were extremely active in mice infected with the reconstructed 1918 flu. The activity of those genes was weaker in animals exposed to just a portion of the 1918 virus. Most of those genes remained inactive in animals infected with the contemporary strain, the group reports online Sept. 27 for an upcoming Nature.
These results suggest that all the genes in the deadly 1918 strain somehow work together to excessively rile the immune system, explains Katze. “Too much of anything is not good,” he says. “One trick of this virus, whether intentional or unintentional, seems to be to excite the host’s immune response” to such an extent that it becomes deadly.
Epidemiologist David Morens of the National Institute of Allergy and Infectious Diseases in Bethesda, Md., notes that figuring out how to modulate such an overwhelming immune response could improve countermeasures against similarly lethal flu strains that might arrive in the future.
“Any attempt to understand what happened with this flu and learn lessons to help us in the future is very important stuff,” he says.