Immune Response Modeling of Interferon β-Pretreated Influenza Virus-Infected Human Dendritic Cells

Abstract

The pretreatment of human dendritic cells with interferon-beta enhances their immune response to influenza virus infection. We measured the expression levels of several key players in that response over a period of 13 h both during pretreatment and after viral infection. Their activation profiles reflect the presence of both negative and positive feedback loops in interferon induction and interferon signaling pathway. Based on these measurements, we have developed a comprehensive computational model of cellular immune response that elucidates its mechanism and its dynamics in interferon-pretreated dendritic cells, and provides insights into the effects of duration and strength of pretreatment.

Cytokine Response Is Determined by Duration of Receptor and Signal Transducers and Activators of Transcription 3 (STAT3) Activation

“…cDNA was synthesized from total RNA using AffinityScript MultiTemp RT (Agilent) with an oligo(dT) 18 primer. Real-time PCR was performed using PlatinumTaq DNA polymerase (Invitrogen) and SYBR Green (Invitrogen) on an ABI7900HT thermal cycler (Applied Biosystems), as described previously (15).…”

“…These models build on previously developed JAK/STAT models (17)(18)(19) and used parameter values from previous models of STAT3 signaling (17). The deterministic versions of these models used a system of coupled ordinary differential equations (ODEs) based on mass action kinetics (similar to the initial models).…”

Biphasic RLR–IFN-β Response Controls the Balance between Antiviral Immunity and Cell Damage

“…The interlinked Cdc42/Cdc24 feedback loop controlling actin polymerization converts continuous inputs into discrete differential outputs and determines the stability of polarized "on" or "off" states (16). In summary, multiple feedback loops often generate nonhomogeneity in response to the homogeneous input signal, hence, controls various cellular response, such as cell fate decision, oscillatory behaviors, and memory of transient input stimulus (16)(17)(18)(19).…”

Model of influenza A virus infection: Dynamics of viral antagonism and innate immune response

“…The present model is built from one [14, 15] we developed for understanding data on infection of human monocyte-derived DCs with influenza virus PR8 after pretreatment with IFNβ, or with Newcastle Disease Virus (NDV) expressing Nipah virus proteins [16, 17]. The similarity of the equations in the two models is the consequence of a common early immune response of DCs.…”