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

Chunmei Cai; Jie Zhou; Xiaoqiang Sun; Tingzhe Sun; Weihong Xie; Jun Cui

doi:10.1371/journal.pone.0186105

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

PLoS One. 2017 Oct 11;12(10):e0186105. doi: 10.1371/journal.pone.0186105. eCollection 2017.

Authors

Chunmei Cai^{1

2}, Jie Zhou¹, Xiaoqiang Sun², Tingzhe Sun³, Weihong Xie¹, Jun Cui^{1

4}

Affiliations

¹ Key Laboratory of Gene Engineering of the Ministry of Education, State Key Laboratory of Biocontrol, School of Life Sciences, Sun Yat-sen University, Guangzhou, P. R. China.
² Zhongshan School of Medicine, Sun Yat-sen University, Guangzhou, P. R. China.
³ AnQing Normal University, AnQing, PR China.
⁴ Collaborative Innovation Center of Cancer Medicine, Sun Yat-sen University, Guangzhou, P. R. China.

Abstract

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.

MeSH terms

A549 Cells
Cell Shape / drug effects
Extracellular Space / metabolism*
Gene Expression Regulation / drug effects
HEK293 Cells
Humans
Interferons / pharmacology*
Intracellular Space / metabolism*
Models, Biological*
Paracrine Communication / drug effects
Time 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

Substances

Transcription Factors
Interferons

Grants and funding

This work was supported by National Natural Science Foundation of China (31522018, 91629101), Guangdong Natural Science Funds for Distinguished Young Scholar (S2013050014772), Guangdong Innovative Research Team Program (NO. 2011Y035 and 201001Y0104687244), Guangzhou Science and Technology Project (201605030012), the Fundamental Research Funds for the Central Universities (15lgjc02), the Training Program for Outstanding Young Teachers in Higher Education institutions of Guangdong Province (YQ2015001), the Guangdong Nature Science Foundation (2014A030310355, 2016A030313234), and the National Natural Science Foundation of China (61503419). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.