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

Amber M Smith, Frederick R Adler, Julie L McAuley, Ryan N Gutenkunst, Ruy M Ribeiro, Jonathan A McCullers and Alan S Perelson

PLOS Computational Biology, 2011, vol. 7, issue 2, 1-12

Abstract: 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.

Date: 2011
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Persistent link: https://EconPapers.repec.org/RePEc:plo:pcbi00:1001081

DOI: 10.1371/journal.pcbi.1001081

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