Abstract
Secretion of type I interferons (IFN) by infected cells mediates protection against many viruses, but prolonged or excessive type I IFN secretion can lead to immune pathology. A proper type I IFN response must therefore maintain a balance between protection and excessive IFN secretion. It has been widely noted that the type I IFN response is driven by positive feedback and is heterogeneous, with only a fraction of infected cells upregulating IFN expression even in clonal cell lines, but the functional roles of feedback and heterogeneity in balancing protection and excessive IFN secretion are not clear. To investigate the functional roles for feedback and heterogeneity, we constructed a mathematical model coupling IFN and viral dynamics that extends existing mathematical models by accounting for feedback and heterogeneity. We fit our model to five existing datasets, reflecting different experimental systems. Fitting across datasets allowed us to compare the IFN response across the systems and suggested different signatures of feedback and heterogeneity in the different systems. Further, through numerical experiments, we generated hypotheses of functional roles for IFN feedback and heterogeneity consistent with our mathematical model. We hypothesize an inherent tradeoff in the IFN response: a positive feedback loop prevents excessive IFN secretion, but also makes the IFN response vulnerable to viral antagonism. We hypothesize that cellular heterogeneity of the IFN response functions to protect the feedback loop from viral antagonism. Verification of our hypotheses will require further experimental studies. Our work provides a basis for analyzing the type I IFN response across systems.
Highlights
Type I interferons (IFN) play a key role in the early immune response to viral infection [1].The type I IFN response can be divided into two components: IFN induction, involving sensing of virus and consequent transcription and secretion of IFNs, and IFN signaling, involving the binding of extracellular IFN to type I IFN receptors and consequent upregulation of antiviral genes
Our model extends current intercellular-based models by accounting for IFN feedback and heterogeneity
We fit our model to several datasets involving different viruses and host cells: in vitro infection of human, epithelial carcinoma cells by mutant and wild-type Dengue virus (DENV) (Schmid et al [41]), in vitro infection of murine fibroblasts by New Castle disease virus (NDV) (Rand et al [40]), in vitro infection of human, monocyte-derived dendritic cells by NDV (Patil et al [47]) and an in vivo infection of ponies by equine influenza A virus (IAV) (Saenz et al [46])
Summary
The type I IFN response can be divided into two components: IFN induction, involving sensing of virus and consequent transcription and secretion of IFNs, and IFN signaling, involving the binding of extracellular IFN to type I IFN receptors and consequent upregulation of antiviral genes. Type I IFN induction begins when viral molecules are sensed by membrane-bound or cytosolic proteins known as pattern recognition receptors (PRRs). Type I IFN signaling begins when extracellular IFN binds to type I IFN receptors, which are found on the surface of almost all cells, leading to activation of the JAK/STAT signaling pathway and upregulation of interferon-stimulated genes (ISGs), a collection of hundreds of genes, many with antiviral properties [6,7]. IFN signaling can occur in an autocrine or paracrine manner, depending on whether a particular IFN protein binds to receptors of the cell that secreted it or other cells, respectively
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