Effect of 1918 PB1-F2 expression on influenza A virus infection kinetics

Title: Effect of 1918 PB1-F2 expression on influenza A virus infection kinetics

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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, and produces enhanced inflammation and increased 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 and select the best model. This model supports a lower viral clearance rate and higher infected cell death rate with the PR8-PB1-F2(1918) virus, although the viral production rate may also be higher. We hypothesize that the higher PR8-PB1-F2(1918) viral titers early in an infection are due to both an increase in viral production withmore »« less

Authors:

Ribeiro, Ruy ^[1]; Perelson, Alan S ^[1]; Smith, Amber M ^[2]; Adler, Frederick R ^[2]; Mcauley, Julie L ^[3]; Mccullers, Jonathan A ^[3]

Los Alamos National Laboratory
UNIV OF UTAH
ST. JUDES CHILDREN RESEARCH

Publication Date:: 2009-01-01

Research Org.:: Los Alamos National Lab. (LANL), Los Alamos, NM (United States)

Sponsoring Org.:: USDOE

OSTI Identifier:: 971324

Report Number(s):: LA-UR-09-06271; LA-UR-09-6271
Journal ID: ISSN 0022-1767; JOIMA3; TRN: US201004%%86

DOE Contract Number:: AC52-06NA25396

Resource Type:: Journal Article

Journal Name:: Journal of Immunology

Additional Journal Information:: Journal Name: Journal of Immunology; Journal ID: ISSN 0022-1767

Country of Publication:: United States

Language:: English

Subject:: 59; APOPTOSIS; CLEARANCE; DEATH; IN VITRO; IN VIVO; INFLAMMATION; INFLUENZA; KINETICS; MATHEMATICAL MODELS; MICE; MONOCYTES; PNEUMONIA; POLYMERASES; PRODUCTION; PROTEINS; VIRULENCE

Citation Formats


                    Ribeiro, Ruy, Perelson, Alan S, Smith, Amber M, Adler, Frederick R, Mcauley, Julie L, and Mccullers, Jonathan A. Effect of 1918 PB1-F2 expression on influenza A virus infection kinetics.  United States: N. p., 2009. 
        Web.

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                    Ribeiro, Ruy, Perelson, Alan S, Smith, Amber M, Adler, Frederick R, Mcauley, Julie L, & Mccullers, Jonathan A. Effect of 1918 PB1-F2 expression on influenza A virus infection kinetics.  United States.

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                    Ribeiro, Ruy, Perelson, Alan S, Smith, Amber M, Adler, Frederick R, Mcauley, Julie L, and Mccullers, Jonathan A. Thu .  
        "Effect of 1918 PB1-F2 expression on influenza A virus infection kinetics".  United States.  https://www.osti.gov/servlets/purl/971324.

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@article{osti_971324,

  title        = {Effect of 1918 PB1-F2 expression on influenza A virus infection kinetics},

  author       = {Ribeiro, Ruy and Perelson, Alan S and Smith, Amber M and Adler, Frederick R and Mcauley, Julie L and Mccullers, Jonathan A},

  abstractNote = {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, and produces enhanced inflammation and increased 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 and select the best model. This model supports a lower viral clearance rate and higher infected cell death rate with the PR8-PB1-F2(1918) virus, although the viral production rate may also be higher. We hypothesize that the higher PR8-PB1-F2(1918) viral titers early in an infection are due to both an increase in viral production with decreased viral clearance, and that the faster decline in the later stages of infection result from elevated cell death rates. We discuss the implications these mechanisms have during an infection with a virus expressing a virulent PBI-F2 on the possibility of a pandemic and on the importance of antiviral treatments.},

  doi          = {},

  url          = {https://www.osti.gov/biblio/971324},
  journal      = {Journal of Immunology},

  issn         = {0022-1767},

  number       = ,

  volume       = ,

  place        = {United States},

  year         = {2009},

  month        = {1}

}

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