Murine Ifit3 restricts the replication of Rabies virus both in vitro and in vivo.

Rabies virus (RABV) infection can initiate the host immune defence response and induce an antiviral state characterized by the expression of interferon (IFN)-stimulated genes (ISGs), among which the family of genes of IFN-induced protein with tetratricopeptide repeats (Ifits) are prominent representatives. Herein, we demonstrated that the mRNA and protein levels of Ifit1, Ifit2 and Ifit3 were highly increased in cultured cells and mouse brains after RABV infection. Recombinant RABV expressing Ifit3, designated rRABV-Ifit3, displayed a lower pathogenicity than the parent RABV in C57BL/6 mice after intramuscular administration, and Ifit3-deficient mice exhibited higher susceptibility to RABV infection and higher mortality during RABV infection. Moreover, compared with their individual expressions, co-expression of Ifit2 and Ifit3 could more effectively inhibit RABV replication in vitro. These results indicate that murine Ifit3 plays an essential role in restricting the replication and reducing the pathogenicity of RABV. Ifit3 acts synergistically with Ifit2 to inhibit RABV replication, providing further insight into the function and complexity of the Ifit family.

[1]  Yingying Li,et al.  A novel antiviral lncRNA, EDAL, shields a T309 O-GlcNAcylation site to promote EZH2 lysosomal degradation , 2020, Genome Biology.

[2]  Yingying Li,et al.  Interferon-λ Attenuates Rabies Virus Infection by Inducing Interferon-Stimulated Genes and Alleviating Neurological Inflammation , 2020, Viruses.

[3]  S. Harrison,et al.  Structure of a rabies virus polymerase complex from electron cryo-microscopy , 2019, Proceedings of the National Academy of Sciences.

[4]  B. Moss,et al.  Vaccinia Virus Ankyrin-Repeat/F-Box Protein Targets Interferon-Induced IFITs for Proteasomal Degradation , 2019, Cell reports.

[5]  G. Cheng,et al.  NF-κB-Dependent IFIT3 Induction by HBx Promotes Hepatitis B Virus Replication , 2019, Front. Microbiol..

[6]  E. Emmott,et al.  Ifit1 regulates norovirus infection and enhances the interferon response in murine macrophage-like cells , 2019, bioRxiv.

[7]  M. Alirezaei,et al.  Biphasic and cardiomyocyte-specific IFIT activity protects cardiomyocytes from enteroviral infection , 2019, PLoS pathogens.

[8]  S. Swaminathan,et al.  Human IFIT proteins inhibit lytic replication of KSHV: A new feed-forward loop in the innate immune system , 2019, PLoS pathogens.

[9]  Chung-Ji Liu,et al.  IFIT1 and IFIT3 promote oral squamous cell carcinoma metastasis and contribute to the anti-tumor effect of gefitinib via enhancing p-EGFR recycling , 2019, Oncogene.

[10]  T. Sweeney,et al.  Better together: the role of IFIT protein-protein interactions in the antiviral response. , 2018, The Journal of general virology.

[11]  M. Diamond,et al.  Human IFIT3 Modulates IFIT1 RNA Binding Specificity and Protein Stability , 2018, Immunity.

[12]  J. Schoggins.  Recent advances in antiviral interferon-stimulated gene biology , 2018, F1000Research.

[13]  E. Emmott,et al.  IFIT3 and IFIT2/3 promote IFIT1-mediated translation inhibition by enhancing binding to non-self RNA , 2018, bioRxiv.

[14]  I. Fraser,et al.  IFIT1 Exerts Opposing Regulatory Effects on the Inflammatory and Interferon Gene Programs in LPS-Activated Human Macrophages , 2018, Cell reports.

[15]  R. Cencic,et al.  Structure of human IFIT1 with capped RNA reveals adaptable mRNA binding and mechanisms for sensing N1 and N2 ribose 2′-O methylations , 2017, Proceedings of the National Academy of Sciences.

[16]  M. Murakami,et al.  Interferon-stimulated gene (ISG) 60, as well as ISG56 and ISG54, positively regulates TLR3/IFN-β/STAT1 axis in U373MG human astrocytoma cells , 2016, Neuroscience Research.

[17]  M. Diamond,et al.  IFIT1 Differentially Interferes with Translation and Replication of Alphavirus Genomes and Promotes Induction of Type I Interferon , 2015, PLoS pathogens.

[18]  M. Diamond,et al.  Innate immune restriction and antagonism of viral RNA lacking 2׳-O methylation , 2015, Virology.

[19]  M. Diamond.  IFIT1: A dual sensor and effector molecule that detects non-2′-O methylated viral RNA and inhibits its translation , 2014, Cytokine & Growth Factor Reviews.

[20]  G. Superti-Furga,et al.  IFITs: Emerging Roles as Key Anti-Viral Proteins , 2014, Front. Immunol..

[21]  C. Hellen,et al.  Inhibition of translation by IFIT family members is determined by their ability to interact selectively with the 5′-terminal regions of cap0-, cap1- and 5′ppp- mRNAs , 2013, Nucleic acids research.

[22]  A. Pichlmair,et al.  Sequestration by IFIT1 Impairs Translation of 2′O-unmethylated Capped RNA , 2013, PLoS pathogens.

[23]  H. Fuchs,et al.  IFIT2 Is an Effector Protein of Type I IFN–Mediated Amplification of Lipopolysaccharide (LPS)-Induced TNF-α Secretion and LPS-Induced Endotoxin Shock , 2013, The Journal of Immunology.

[24]  N. Reich.  A death-promoting role for ISG54/IFIT2. , 2013, Journal of interferon & cytokine research : the official journal of the International Society for Interferon and Cytokine Research.

[25]  Xiaoping Zhou,et al.  Interferon Induced IFIT Family Genes in Host Antiviral Defense , 2013, International journal of biological sciences.

[26]  Giulio Superti-Furga,et al.  Structural basis for viral 5′-PPP-RNA recognition by human IFIT proteins , 2013, Nature.

[27]  M. Habjan,et al.  ISG56/IFIT1 is primarily responsible for interferon-induced changes to patterns of parainfluenza virus type 5 transcription and protein synthesis , 2013, The Journal of general virology.

[28]  S. Rayner,et al.  National Borders Effectively Halt the Spread of Rabies: The Current Rabies Epidemic in China Is Dislocated from Cases in Neighboring Countries , 2013, PLoS neglected tropical diseases.

[29]  M. Diamond,et al.  The broad-spectrum antiviral functions of IFIT and IFITM proteins , 2012, Nature Reviews Immunology.

[30]  Y. Li,et al.  Crystal structure of ISG54 reveals a novel RNA binding structure and potential functional mechanisms , 2012, Cell Research.

[31]  Antonio Sanfilippo,et al.  Identification and Validation of Ifit1 as an Important Innate Immune Bottleneck , 2012, PloS one.

[32]  M. Diamond,et al.  2′-O Methylation of the Viral mRNA Cap by West Nile Virus Evades Ifit1-Dependent and -Independent Mechanisms of Host Restriction In Vivo , 2012, PLoS pathogens.

[33]  M. Diamond,et al.  Interferon-Induced Ifit2/ISG54 Protects Mice from Lethal VSV Neuropathogenesis , 2012, PLoS pathogens.

[34]  Wei Chen,et al.  IFN-Induced TPR Protein IFIT3 Potentiates Antiviral Signaling by Bridging MAVS and TBK1 , 2011, The Journal of Immunology.

[35]  G. Superti-Furga,et al.  IFIT1 is an antiviral protein that recognizes 5′-triphosphate RNA , 2011, Nature Immunology.

[36]  G. Sen,et al.  The ISG56/IFIT1 gene family. , 2011, Journal of interferon & cytokine research : the official journal of the International Society for Interferon and Cytokine Research.

[37]  Hongping Dong,et al.  2′-O methylation of the viral mRNA cap evades host restriction by IFIT family members , 2010, Nature.

[38]  M. Gale,et al.  Rabies Virus Infection Induces Type I Interferon Production in an IPS-1 Dependent Manner While Dendritic Cell Activation Relies on IFNAR Signaling , 2010, PLoS pathogens.

[39]  Huanchun Chen,et al.  The Roles of Chemokines in Rabies Virus Infection: Overexpression May Not Always Be Beneficial , 2009, Journal of Virology.

[40]  H. Shu,et al.  ISG56 is a negative-feedback regulator of virus-triggered signaling and cellular antiviral response , 2009, Proceedings of the National Academy of Sciences.

[41]  I. Autenrieth,et al.  Forced IFIT-2 expression represses LPS induced TNF-alpha expression at posttranscriptional levels , 2008, BMC Immunology.

[42]  G. Sen,et al.  Interferon‐inducible protein, P56, inhibits HPV DNA replication by binding to the viral protein E1 , 2008, The EMBO journal.

[43]  G. Sen,et al.  Induction and mode of action of the viral stress-inducible murine proteins, P56 and P54. , 2005, Virology.

[44]  J. Hiscott,et al.  Transcriptional Profiling of Interferon Regulatory Factor 3 Target Genes: Direct Involvement in the Regulation of Interferon-Stimulated Genes , 2002, Journal of Virology.

[45]  Yamamura Ken-ichi,et al.  Efficient selection for high-expression transfectants with a novel eukaryotic vector , 1991 .