Immune response modeling of interferon beta-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.

Figure 1

Induction of IFNs after virus infection in IFN-β pretreated human DCs. IFN-β, after binding to IFNAR, engages the JAK/STAT pathway, leading to STAT phosphorylation and production of IRF7 and SOCS. The latter acts back negatively on JAK/STAT pathway activation. Viral infection is detected by RIG-I and leads via IRF7 activation to induction and secretion of IFN-β/α, which bind to IFNAR in a positive feedback loop. Protein tyrosine phosphatases (PTPs) act in the cytoplasm and nucleus.

Figure 2

Experiment and simulation of IFN-pretreated DC response to influenza PR8 virus infection. The experimental time course data points are marked by crosses and connected with dashed lines after normalization with respect to the corresponding maximum for each species in (A) nuclear protein, (B–E) mRNA, and (F) secreted protein. The label of the horizontal axis represents the time (in hours) of measurement. The simulation result is plotted with solid lines and normalized to the corresponding maximum. The temporal response of each species is divided into three stages according to the change in extracellular IFN level (as discussed in the text), separated by vertical lines. Pretreatment time extends from t = −3 to t = 0 h. Viral infection (PR8 virus) takes place at t = 0 h. The DCs used in the experiment are from four different donors, denoted as donors 1–4 in this legend. The data points for t = −3–0 h in A are the average results from donors 1–3. The data points for t = 2–8 h in A are from donor 1. The data points for t = −3–0 h in B–F are the average results from donors 2 and 3. The data points for t = 2–10 h in B–F are from donor 4.

Figure 3

Predicted dependence of IFN induction on IFN pretreatment conditions. (A) IFN mRNA levels are evaluated at t = 10 h for increasing IFN pretreatment dosages and indicated pretreatment times. The computed IFN mRNA levels are normalized by the value computed at the pretreatment condition of 50 U/ml dosage and 6 h of pretreatment. (B) Predicted temporal responses of STAT1Pn and IRF7Pn level at indicated pretreatment dosages for a pretreatment duration of 3 h.

Figure 4

Simulations of the temporal IFN response to virus infection under in vitro IFN pretreatment and in vivo IFN priming conditions. (A) The temporal behavior of IRF7 mRNA. (B) The temporal behavior of IFN-β mRNA. Virus infection is introduced at t = 0. For the in vitro case, an IFN pretreatment dosage of 20 U/ml with a pretreatment time of 3 h is used. The concentration of the infected DCs is set to 5 × 10⁵ cells/ml, as in Fig. 2. For the in vivo simulation, a constant extracellular IFN level of 20 U/ml is used, and the priming time is set to 3 h.