Effect of 1918 PB1-F2 Expression on Influenza A Virus Infection Kinetics

Relatively little is known about the viral factors contributing to the lethality of the 1918 pandemic, although its unparalleled virulence was likely due in part to the newly discovered PB1-F2 protein. This protein, while unnecessary for replication, increases apoptosis in monocytes, alters viral polymerase activity in vitro, enhances inflammation and increases secondary pneumonia in vivo. However, the effects the PB1-F2 protein have in vivo remain unclear. To address the mechanisms involved, we intranasally infected groups of mice with either influenza A virus PR8 or a genetically engineered virus that expresses the 1918 PB1-F2 protein on a PR8 background, PR8-PB1-F2(1918). Mice inoculated with PR8 had viral concentrations peaking at 72 hours, while those infected with PR8-PB1-F2(1918) reached peak concentrations earlier, 48 hours. Mice given PR8-PB1-F2(1918) also showed a faster decline in viral loads. We fit a mathematical model to these data to estimate parameter values. The model supports a higher viral production rate per cell and a higher infected cell death rate with the PR8-PB1-F2(1918) virus. We discuss the implications these mechanisms have during an infection with a virus expressing a virulent PB1-F2 on the possibility of a pandemic and on the importance of antiviral treatments.Author Summary: Influenza A virus is a respiratory pathogen that causes significant morbidity and mortality in infected individuals, particularly during pandemics like the 1918–1919 Spanish Flu pandemic. Recent data suggests that the influenza virus PB1-F2 protein contributes to disease severity. Here, we use data from infected mice together with quantitative analyses to understand how the PB1-F2 protein from the 1918–1919 pandemic strain influences viral kinetics. We find that the rates of virus growth and decay are increased when the 1918 PB1-F2 is present. Our analyses suggest that infection with an influenza virus possessing the 1918 PB1-F2 protein results in a higher rate of viral production from infected cells and a higher rate of infected cell death. These results provide new insights into the mechanisms of PB1-F2 and the virulence and pathogenesis of pandemic strains of influenza.