Systematic Identification of Type I and Type II Interferon-induced Antiviral Factors

Overview

Journal Proc Natl Acad Sci U S A

Specialty Science

Date 2012 Feb 29

PMID 22371602

Citations 287

Authors

Su-Yang Liu

David Jesse Sanchez

Roghiyh Aliyari

Sun Lu

Genhong Cheng

Affiliations

Soon will be listed here.

Abstract

Type I and type II interferons (IFNs) are cytokines that establish the cellular antiviral state through the induction of IFN-stimulated genes (ISGs). We sought to understand the basis of the antiviral activity induced by type I and II IFNs in relation to the functions of their ISGs. Based on gene expression studies, we systematically identified antiviral ISGs by performing blinded, functional screens on 288 type I and type II ISGs. We assessed and validated the antiviral activity of these ISGs against an RNA virus, vesicular stomatitis virus (VSV), and a DNA virus, murine gammaherpes virus (MHV-68). Overall, we identified 34 ISGs that elicited an antiviral effect on the replication of either one or both viruses. Fourteen ISGs have uncharacterized antiviral functions. We further defined ISGs that affect critical life-cycle processes in expression of VSV protein and MHV-68 immediate-early genes. Two previously undescribed antiviral ISGs, TAP1 and BMP2, were further validated. TAP1-deficient fibroblasts were more susceptible to VSV infection but less so to MHV-68 infection. On the other hand, exogenous BMP2 inhibits MHV-68 lytic growth but did not affect VSV growth. These results delineate common and distinct sets of type I and type II IFN-induced genes as well as identify unique ISGs that have either broad or specific antiviral effects on these viruses.

Citing Articles

Integrated transcriptomic profiling reveals a STING-mediated Type II Interferon signature in SOD1-mutant amyotrophic lateral sclerosis models.

Hiew J, Lim Y, Liu H, Ng C Commun Biol. 2025; 8(1):347.

PMID: 40025162 PMC: 11873215. DOI: 10.1038/s42003-025-07790-w.

ISG15-Dependent Stabilisation of USP18 Is Necessary but Not Sufficient to Regulate Type I Interferon Signalling in Humans.

Vasou A, Nightingale K, Cetkovska V, Scheler J, Bamford C, Andrejeva J Eur J Immunol. 2025; 55(2):e202451651.

PMID: 39931755 PMC: 11811815. DOI: 10.1002/eji.202451651.

Regulation of viral replication by host restriction factors.

Lin Y, Zhu Y, Jing L, Lei X, Xie Z Front Immunol. 2025; 16:1484119.

PMID: 39917304 PMC: 11798991. DOI: 10.3389/fimmu.2025.1484119.

Research Progress on the Structure and Function, Immune Escape Mechanism, Antiviral Drug Development Methods, and Clinical Use of SARS-CoV-2 M.

Ren J, Zhang Z, Xia Y, Zhao D, Li D, Zhang S Molecules. 2025; 30(2).

PMID: 39860219 PMC: 11767629. DOI: 10.3390/molecules30020351.

IFN- signaling is required for the efficient replication of murine hepatitis virus (MHV) strain JHM in the brains of infected mice.

Kerr C, Proctor-Roser M, Parthasarathy S, OConnor J, Pfannenstiel J, Orozco R bioRxiv. 2025; .

PMID: 39803452 PMC: 11722247. DOI: 10.1101/2025.01.01.631031.

References

Zarnegar B, Wang Y, Mahoney D, Dempsey P, Cheung H, He J . Noncanonical NF-kappaB activation requires coordinated assembly of a regulatory complex of the adaptors cIAP1, cIAP2, TRAF2 and TRAF3 and the kinase NIK. Nat Immunol. 2008; 9(12):1371-8. PMC: 2676931. DOI: 10.1038/ni.1676. View

Scherle P, Dorshkind K, Witte O . Clonal lymphoid progenitor cell lines expressing the BCR/ABL oncogene retain full differentiative function. Proc Natl Acad Sci U S A. 1990; 87(5):1908-12. PMC: 53593. DOI: 10.1073/pnas.87.5.1908. View

Yamaguchi K, NAGAI S, Ninomiya-Tsuji J, Nishita M, Tamai K, Irie K . XIAP, a cellular member of the inhibitor of apoptosis protein family, links the receptors to TAB1-TAK1 in the BMP signaling pathway. EMBO J. 1999; 18(1):179-87. PMC: 1171113. DOI: 10.1093/emboj/18.1.179. View

Negrete O, Levroney E, Aguilar H, Bertolotti-Ciarlet A, Nazarian R, Tajyar S . EphrinB2 is the entry receptor for Nipah virus, an emergent deadly paramyxovirus. Nature. 2005; 436(7049):401-5. DOI: 10.1038/nature03838. View

Takada A, Robison C, Goto H, Sanchez A, Murti K, Whitt M . A system for functional analysis of Ebola virus glycoprotein. Proc Natl Acad Sci U S A. 1998; 94(26):14764-9. PMC: 25111. DOI: 10.1073/pnas.94.26.14764. View

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

Boname J, de Lima B, Lehner P, Stevenson P . Viral degradation of the MHC class I peptide loading complex. Immunity. 2004; 20(3):305-17. DOI: 10.1016/s1074-7613(04)00047-0. View

Yoneyama M, Kikuchi M, Matsumoto K, Imaizumi T, Miyagishi M, Taira K . Shared and unique functions of the DExD/H-box helicases RIG-I, MDA5, and LGP2 in antiviral innate immunity. J Immunol. 2005; 175(5):2851-8. DOI: 10.4049/jimmunol.175.5.2851. View

van den Broek M, Muller U, Huang S, Zinkernagel R, Aguet M . Immune defence in mice lacking type I and/or type II interferon receptors. Immunol Rev. 1995; 148:5-18. DOI: 10.1111/j.1600-065x.1995.tb00090.x. View

10.

Wu T, Usherwood E, Stewart J, Nash A, Sun R . Rta of murine gammaherpesvirus 68 reactivates the complete lytic cycle from latency. J Virol. 2000; 74(8):3659-67. PMC: 111876. DOI: 10.1128/jvi.74.8.3659-3667.2000. View

11.

Muller U, Steinhoff U, Reis L, Hemmi S, Pavlovic J, Zinkernagel R . Functional role of type I and type II interferons in antiviral defense. Science. 1994; 264(5167):1918-21. DOI: 10.1126/science.8009221. View

12.

Flano E, Kim I, Woodland D, Blackman M . Gamma-herpesvirus latency is preferentially maintained in splenic germinal center and memory B cells. J Exp Med. 2002; 196(10):1363-72. PMC: 2193987. DOI: 10.1084/jem.20020890. View

13.

Xie Z, Shao S, Lv J, Wang C, Yuan C, Zhang W . Co-transfection and tandem transfection of HEK293A cells for overexpression and RNAi experiments. Cell Biol Int. 2010; 35(3):187-92. DOI: 10.1042/CBI20100470. View

14.

Sarawar S, Cardin R, Brooks J, Mehrpooya M, Mo X, Doherty P . Gamma interferon is not essential for recovery from acute infection with murine gammaherpesvirus 68. J Virol. 1997; 71(5):3916-21. PMC: 191543. DOI: 10.1128/JVI.71.5.3916-3921.1997. View

15.

Taniguchi T, Takaoka A . The interferon-alpha/beta system in antiviral responses: a multimodal machinery of gene regulation by the IRF family of transcription factors. Curr Opin Immunol. 2002; 14(1):111-6. DOI: 10.1016/s0952-7915(01)00305-3. View

16.

Sadler A, Williams B . Interferon-inducible antiviral effectors. Nat Rev Immunol. 2008; 8(7):559-68. PMC: 2522268. DOI: 10.1038/nri2314. View

17.

Schoggins J, Wilson S, Panis M, Murphy M, Jones C, Bieniasz P . A diverse range of gene products are effectors of the type I interferon antiviral response. Nature. 2011; 472(7344):481-5. PMC: 3409588. DOI: 10.1038/nature09907. View

18.

Wang X, Lybarger L, Connors R, Harris M, Hansen T . Model for the interaction of gammaherpesvirus 68 RING-CH finger protein mK3 with major histocompatibility complex class I and the peptide-loading complex. J Virol. 2004; 78(16):8673-86. PMC: 479079. DOI: 10.1128/JVI.78.16.8673-8686.2004. View

19.

Meraz M, White J, Sheehan K, Bach E, Rodig S, Dighe A . Targeted disruption of the Stat1 gene in mice reveals unexpected physiologic specificity in the JAK-STAT signaling pathway. Cell. 1996; 84(3):431-42. DOI: 10.1016/s0092-8674(00)81288-x. View

20.

Schroder K, Hertzog P, Ravasi T, Hume D . Interferon-gamma: an overview of signals, mechanisms and functions. J Leukoc Biol. 2003; 75(2):163-89. DOI: 10.1189/jlb.0603252. View