Integrated Modeling and Analysis of Intracellular and Intercellular Mechanisms in Shaping the Interferon Response to Viral Infection

Overview

Journal PLoS One

Specialties General Medicine
Science

Date 2017 Oct 12

PMID 29020068

Citations 3

Authors

Chunmei Cai

Jie Zhou

Xiaoqiang Sun

Tingzhe Sun

Weihong Xie

Jun Cui

Affiliations

Soon will be listed here.

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.

Citing Articles

A Review of Using Mathematical Modeling to Improve Our Understanding of Bacteriophage, Bacteria, and Eukaryotic Interactions.

Styles K, Brown A, Sagona A Front Microbiol. 2021; 12:724767.

PMID: 34621252 PMC: 8490754. DOI: 10.3389/fmicb.2021.724767.

A mathematic model to reveal delicate cross-regulation between MAVS/STING, inflammasome and MyD88-dependent type I interferon signalling.

Cai C, Yu X J Cell Mol Med. 2020; 24(19):11535-11545.

PMID: 32885594 PMC: 7576308. DOI: 10.1111/jcmm.15768.

Investigating Functional Roles for Positive Feedback and Cellular Heterogeneity in the Type I Interferon Response to Viral Infection.

Leviyang S, Griva I Viruses. 2018; 10(10).

PMID: 30241427 PMC: 6213501. DOI: 10.3390/v10100517.

References

Sheppard P, Kindsvogel W, Xu W, Henderson K, Schlutsmeyer S, Whitmore T . IL-28, IL-29 and their class II cytokine receptor IL-28R. Nat Immunol. 2002; 4(1):63-8. DOI: 10.1038/ni873. View

Xu L, Wang Y, Han K, Li L, Zhai Z, Shu H . VISA is an adapter protein required for virus-triggered IFN-beta signaling. Mol Cell. 2005; 19(6):727-40. DOI: 10.1016/j.molcel.2005.08.014. View

Lichty B, Power A, Stojdl D, Bell J . Vesicular stomatitis virus: re-inventing the bullet. Trends Mol Med. 2004; 10(5):210-6. DOI: 10.1016/j.molmed.2004.03.003. View

Chen S, Short J, Young D, Killip M, Schneider M, Goodbourn S . Heterocellular induction of interferon by negative-sense RNA viruses. Virology. 2010; 407(2):247-55. PMC: 2963793. DOI: 10.1016/j.virol.2010.08.008. View

Bolen C, Ding S, Robek M, Kleinstein S . Dynamic expression profiling of type I and type III interferon-stimulated hepatocytes reveals a stable hierarchy of gene expression. Hepatology. 2013; 59(4):1262-72. PMC: 3938553. DOI: 10.1002/hep.26657. View

Reikine S, Nguyen J, Modis Y . Pattern Recognition and Signaling Mechanisms of RIG-I and MDA5. Front Immunol. 2014; 5:342. PMC: 4107945. DOI: 10.3389/fimmu.2014.00342. View

Kawai T, Akira S . Innate immune recognition of viral infection. Nat Immunol. 2006; 7(2):131-7. DOI: 10.1038/ni1303. View

Kotenko S . IFN-λs. Curr Opin Immunol. 2011; 23(5):583-90. PMC: 3196341. DOI: 10.1016/j.coi.2011.07.007. View

Fitzgerald K, McWhirter S, Faia K, Rowe D, Latz E, Golenbock D . IKKepsilon and TBK1 are essential components of the IRF3 signaling pathway. Nat Immunol. 2003; 4(5):491-6. DOI: 10.1038/ni921. View

10.

Pestka S, Krause C, Walter M . Interferons, interferon-like cytokines, and their receptors. Immunol Rev. 2004; 202:8-32. DOI: 10.1111/j.0105-2896.2004.00204.x. View

11.

Zinzula L, Tramontano E . Strategies of highly pathogenic RNA viruses to block dsRNA detection by RIG-I-like receptors: hide, mask, hit. Antiviral Res. 2013; 100(3):615-35. PMC: 7113674. DOI: 10.1016/j.antiviral.2013.10.002. View

12.

Miyamoto M, Fujita T, Kimura Y, Maruyama M, Harada H, Sudo Y . Regulated expression of a gene encoding a nuclear factor, IRF-1, that specifically binds to IFN-beta gene regulatory elements. Cell. 1988; 54(6):903-13. DOI: 10.1016/s0092-8674(88)91307-4. View

13.

Shalek A, Satija R, Shuga J, Trombetta J, Gennert D, Lu D . Single-cell RNA-seq reveals dynamic paracrine control of cellular variation. Nature. 2014; 510(7505):363-9. PMC: 4193940. DOI: 10.1038/nature13437. View

14.

Rand U, Rinas M, Schwerk J, Nohren G, Linnes M, Kroger A . Multi-layered stochasticity and paracrine signal propagation shape the type-I interferon response. Mol Syst Biol. 2012; 8:584. PMC: 3377992. DOI: 10.1038/msb.2012.17. View

15.

Wu W, Wang F, Chang M . Dynamic sensitivity analysis of biological systems. BMC Bioinformatics. 2008; 9 Suppl 12:S17. PMC: 2638157. DOI: 10.1186/1471-2105-9-S12-S17. View

16.

Zhang W, Tian T, Zou X . Negative feedback contributes to the stochastic expression of the interferon-β gene in virus-triggered type I interferon signaling pathways. Math Biosci. 2015; 265:12-27. DOI: 10.1016/j.mbs.2015.04.003. View

17.

Pagliaccetti N, Chu E, Bolen C, Kleinstein S, Robek M . Lambda and alpha interferons inhibit hepatitis B virus replication through a common molecular mechanism but with different in vivo activities. Virology. 2010; 401(2):197-206. PMC: 2864496. DOI: 10.1016/j.virol.2010.02.022. View

18.

Doyle S, Schreckhise H, Khuu-Duong K, Henderson K, Rosler R, Storey H . Interleukin-29 uses a type 1 interferon-like program to promote antiviral responses in human hepatocytes. Hepatology. 2006; 44(4):896-906. DOI: 10.1002/hep.21312. View

19.

Hwang S, Hur K, Kim J, Cho K, Kim S, Yoo J . Biphasic RLR-IFN-β response controls the balance between antiviral immunity and cell damage. J Immunol. 2013; 190(3):1192-200. DOI: 10.4049/jimmunol.1202326. View

20.

Loo Y, Gale Jr M . Immune signaling by RIG-I-like receptors. Immunity. 2011; 34(5):680-92. PMC: 3177755. DOI: 10.1016/j.immuni.2011.05.003. View