DC immune responses to NDV-Nipah chimeras virus infection

The ordinary differential equation (ODE) model describes experimental results for human monocyte derived dendritic cells (DCs) infected by individual Nipah virus immune antagonists (P, V, and W) expressed in recombinant Newcastle disease viruses. W antagonizes cellular immune response in the nucleus, whereas P and V do so in the cytoplasm. All three act in both the signaling pathway leading to interferon induction, and the Jak/Stat pathway set into motion by secreted interferon binding to surface receptors. The reaction network is shown below. The model contains 14 species and 49 parameters, of which only the few most sensitive ones were varied to fit the data. The equations of the model are given below. The model aims to capture the essential characteristics of the experimental time-course data for seven of the measured species, namely IFNβm (mRNA of IFNβ), IFNαm (mRNA of IFNα), TNFαm (mRNA of TNFα), IFNαenv (IFNα secreted into the extracellular environment), TNFαenv (TNFα secreted into the extracellular environment), CCL4m (mRNA of CCL4) and CCL5m (mRNA of CCL5). These cytokines and chemokines signal the state of activation of the DC, and serve as markers of the strength of the antiviral response and the effects of viral antagonism. The amount of IFNαm, which depends on activated IRF7, itself induced in the Jak/Stat pathway, reflects the strength of that pathway (as does IFNβ at times after viral infection) , whereas the induction of TNFα, CCL4 and CCL5 (as well as of IFNβ) is influenced by activation of the complex signaling network attached to viral sensors. The model consists of three spatial compartments; cytoplasm, nucleus, and extra-cellular space with membrane receptors for IFNα/β and TNFα.


Contributions from other dendritic cells to extra-cellular amounts of IFNα/βenv and TNFαenv are taken into account in the equations by the factor C which denotes the concentration of virus infected DCs. The form of the equations incorporates a number of simplifying assumptions, the details of which can be found in the published paper and its supplementary material in the Journal of Virology (2010).