Type 1 interferons, a family of proteins that trigger the body's immune responses to many pathogens, can drive inflammation, lung damage and even death in influenza infection, according to new research from the Medical Research Council's National Institute for Medical Research (NIMR; now part of the Francis Crick Institute).
Dr Andreas Wack of NIMR explained: "The severity of disease caused by influenza varies hugely - ranging from mild symptoms to death. What determines the severity is unclear, but the ability of different virus strains to cause disease and the age or immune status of infected individuals are all thought to play a part.
"The role of genetically-determined factors in infected people is less well understood. Clusters of severe flu within families suggest that some people are more susceptible than others. Studies in mice show a wide range of genetic susceptibility - and many genes have been proposed to contribute to susceptibility or resistance."
Type 1 interferons are widely recognised as having an antiviral function in many virus infections, and are known to block influenza virus replication in the laboratory. However, it is less clear what the effect of interferons are in an influenza-infected organism in real life.
Dr Wack's team at NIMR studied mice of different genetic backgrounds to show a direct correlation between high rates of illness and death and high levels of type 1 interferon in response to influenza infection. While a moderate type 1 interferon response contributes to protection during influenza infection, strains of mice with a genetic propensity for a high type 1 interferon response experienced high levels of inflammatory molecules and cells, leading to severe lung damage.
In these susceptible mice with high type 1 interferons, stopping type 1 interferon signalling or removing the cells which produce them reduced influenza induced illness and death.
Dr Wack said: "When virologists think of interferons, they think of antiviral effects, and this is how they were discovered. We were therefore very surprised when we found that high levels of type 1 interferon do not protect but have a disease-causing effect in influenza infection. Under these circumstances, the inflammatory effect of type I interferons overrides their antiviral function, causing more harm than good."
PhD student Sophia Davidson of NIMR added: "We think our observations have important implications for predicting susceptibility to severe flu in humans and for treating the disease caused by this infection.
"Some people may have high numbers of the cells that produce type 1 interferon or a predisposition to strong interferon responses, and this may be a risk factor for severe influenza. We are now trying to understand whether this is in fact the case."
The paper, Pathogenic potential of interferon ?? in acute influenza infection, is published in Nature Communications.