Integrated modeling and analysis of intracellular and intercellular mechanisms in shaping the interferon response to viral infection

• Published in: PloS one Vol. 12; no. 10; p. e0186105
• Main Authors: Cai, Chunmei, Zhou, Jie, Sun, Xiaoqiang, Sun, Tingzhe, Xie, Weihong, Cui, Jun
• Format: Journal Article
• Language: English
• Published: United States Public Library of Science 11.10.2017; Public Library of Science (PLoS)
• Subjects: A549 Cells; Antiviral agents; Biology and Life Sciences; Care and treatment; Cell Shape - drug effects; Computer simulation; Diagnosis; Dosage and administration; Extracellular Space - metabolism; Gene Expression Regulation - drug effects; Health aspects; HEK293 Cells; Heterogeneity; Humans; Infections; Interferon; Interferons - pharmacology; Intracellular; Intracellular Space - metabolism; Laboratories; Medical research; Medicine and Health Sciences; Models, Biological; Paracrine Communication - drug effects; Paracrine signalling; Polymerase chain reaction; Simulation; Studies; Time Factors; Transcription activation; Transcription factors; Transcription Factors - metabolism; Transcriptional Activation - drug effects; Transcriptional Activation - genetics; Vesicular Stomatitis - genetics; Vesicular Stomatitis - metabolism; Vesicular Stomatitis - pathology; Vesiculovirus - drug effects; Vesiculovirus - physiology; Viral infections; Virus diseases; Viruses
• ISSN: 1932-6203; 1932-6203
• DOI: 10.1371/journal.pone.0186105

The interferons (IFNs) responses to viral infection are heterogeneous, while the underlying mechanisms for variability among cells are still not clear. In this study, we developed a hybrid model to systematically identify the sources of IFN induction heterogeneity. The experiment-integrated simulation demonstrated that the viral dose/type, the diversity in transcriptional factors activation and the intercellular paracrine signaling could strikingly shape the heterogeneity of IFN expression. We further determined that the IFNβ and IFNλ1 induced diverse dynamics of IFN-stimulated genes (ISGs) production. Collectively, our findings revealed the intracellular and intercellular mechanisms contributing to cell-to-cell variation in IFN induction, and further demonstrated the significant effects of IFN heterogeneity on antagonizing viruses.