A predictive mathematical model of influenza kinetics with an innate immune response
College of Liberal Arts and Sciences
Physical Sciences and Mathematics
A recent experimental-theoretical collaboration utilized mathematical model-fitting of in vitro data to determine strain-specific parameters of influenza virus infection kinetics [Pinilla et. al., J Virol 86 (2012)]. The parameter sets obtained --- including the average eclipse phase and standard deviation, the viral production rate of a cell and the rate constant for infection --- were complete in that the calibrated model could accurately simulate independent experiments (including multiple-strain infections) without additional parameters. It was determined, e.g., that the NA-H275Y (oseltamivir-resistant) strain of 2009 pandemic influenza has an average eclipse phase 2.5h longer its wild-type counterpart (P=0.013), compromising in vitro fitness. It is the broad goal of mathematical modelers to obtain similarly precise, quantitative specifications of influenza virus replication in vivo, allowing for the rapid determination of clinically-relevant information on emerging virus strains. This will require accounting for the host immune response, in particular the early-time innate immune (i.e., IFN-mediated) effects, within the context of the model. In this study we modify the "target-cell--limited" virus infection model (appropriate to the in vitro setting, where an infection resolves via culture decimation) to include type I interferon production and its antiviral effects. We demonstrate that simulated infections with this model involve the rescue of a large sub-population of susceptible cells and large-scale viral production is curtailed as observed in vivo (e.g., [Seo et. al., Nat Med 8 (2002); Handel et. al. J R Soc Inter 7 (2010)]). Using viral kinetic data from the literature, together with the prior parametrization in vitro, we are able to fully characterize the typical early-time in vivo infection. In continuing work, we consider the implementation of a late-time adaptive immune response necessary to clear the infection.
Innate Immunity to Viral Infections
Holder, Benjamin, "A predictive mathematical model of influenza kinetics with an innate immune response" (2014). Faculty Scholarly Dissemination Grants. 891.