title: The inflammatory response to influenza A virus (H1N1): An experimental and mathematical study.
abstract: Mortality from influenza infections continues as a global public health issue, with the host inflammatory response contributing to fatalities related to the primary infection. Based on Ordinary Differential Equation (ODE) formalism, a computational model was developed for the in-host response to influenza A virus, merging inflammatory, innate, adaptive and humoral responses to virus and linking severity of infection, the inflammatory response, and mortality. The model was calibrated using dense cytokine and cell data from adult BALB/c mice infected with the H1N1 influenza strain A/PR/8/34 in sublethal and lethal doses. Uncertainty in model parameters and disease mechanisms was quantified using Bayesian inference and ensemble model methodology that generates probabilistic predictions of survival, defined as viral clearance and recovery of the respiratory epithelium. The ensemble recovers the expected relationship between magnitude of viral exposure and the duration of survival, and suggests mechanisms primarily responsible for survival, which could guide the development of immuno-modulatory interventions as adjuncts to current anti-viral treatments. The model is employed to extrapolate from available data survival curves for the population and their dependence on initial viral aliquot. In addition, the model allows us to illustrate the positive effect of controlled inflammation on influenza survival.
authors.affiliation: Department of Mathematics, University of Pittsburgh, Pittsburgh, PA, USA.
authors.forename: Ian
authors.initials: I
authors.lastname: Price
authors.affiliation: Department of Computational and Systems Biology, University of Pittsburgh, Pittsburgh, PA, USA.
authors.forename: Ericka D
authors.initials: ED
authors.lastname: Mochan-Keef
authors.affiliation: Department of Mathematics, University of Pittsburgh, Pittsburgh, PA, USA; Department of Computational and Systems Biology, University of Pittsburgh, Pittsburgh, PA, USA.
authors.forename: David
authors.initials: D
authors.lastname: Swigon
authors.affiliation: Department of Mathematics, University of Pittsburgh, Pittsburgh, PA, USA; Department of Computational and Systems Biology, University of Pittsburgh, Pittsburgh, PA, USA.
authors.forename: G Bard
authors.initials: GB
authors.lastname: Ermentrout
authors.affiliation: Department of Mathematics, University of Pittsburgh, Pittsburgh, PA, USA; Department of Critical Care Medicine, University of Pittsburgh, Pittsburgh, PA, USA.
authors.forename: Sarah
authors.initials: S
authors.lastname: Lukens
authors.affiliation: Center for Vaccine Research, University of Pittsburgh, Pittsburgh, PA, USA.
authors.forename: Franklin R
authors.initials: FR
authors.lastname: Toapanta
authors.affiliation: Center for Vaccine Research, University of Pittsburgh, Pittsburgh, PA, USA.
authors.forename: Ted M
authors.initials: TM
authors.lastname: Ross
authors.affiliation: Department of Critical Care Medicine, University of Pittsburgh, Pittsburgh, PA, USA. Electronic address: cler@pitt.edu.
authors.forename: Gilles
authors.initials: G
authors.lastname: Clermont
mesh_terms: D000818:Animals; D001499:Bayes Theorem; D003198:Computer Simulation; D016207:Cytokines / Q000378:metabolism; D005260:Female; D006801:Humans; D007113:Immunity, Innate; D007249:Inflammation / Q000821:virology*; D053118:Influenza A Virus, H1N1 Subtype / Q000502:physiology*; D007251:Influenza, Human / Q000276:immunology; D051379:Mice; D008807:Mice, Inbred BALB C; D008954:Models, Biological; D009010:Monte Carlo Method; D009976:Orthomyxoviridae Infections / Q000276:immunology*; D011336:Probability; D017382:Reactive Oxygen Species / Q000378:metabolism
chemical_list: D016207:Cytokines; D017382:Reactive Oxygen Species
keywords: Bayesian inference; Immune response; Inflammation; Mathematical model; Survival curve
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