Abstract 1407: Interferon Regulatory Factor-9 (irf-9) Mediates Short Term Host Protection, But Promotes Long Term Immune Injury In Evolution Of Myocarditis Leading To Dilated Cardiomyopathy

Circulation ◽  
2007 ◽  
Vol 116 (suppl_16) ◽  
Author(s):  
Michael Konviser ◽  
Youan Liu ◽  
Manyin Chen ◽  
Yu Shi ◽  
Mei Sun ◽  
...  
Keyword(s):  
Innate Immunity ◽  
Cardiac Hypertrophy ◽  
Type I Interferon ◽  
Interferon Regulatory Factor ◽  
Acquired Immunity ◽  
Type I ◽  
Interferon Production ◽  
Wild Type ◽  
Regulatory Factor ◽  
Host Protection

INTRODUCTION: Evolution of viral myocarditis to dilated cardiomyopathy (DCM) represents a delicate balance between host innate immunity and T-cell acquired immunity. IRF-9 is a key member of a transcription factor family that regulates type I interferon (IFN) production, critical for innate antiviral protection. However, the influence of innate immunity in general and IRF-9 in particular on acquired immunity and DCM is unknown. HYPOTHESIS: IRF-9 signaling provides immediate host protection through interferon production, but stimulates acquired immunity leading to DCM in a coxsackievirus murine myocarditis model. METHODS: Interferon-regulatory factor 9 (IRF-9) homozygous knockout mice were generated, and show impaired type I interferon production. Wild-type (WT, n=51) and IRF-9 −/− (n=124) littermates were inoculated with 10^2 p.f.u. of coxsackievirus B3 as previously described. Survival, viral titers, cardiac hypertrophy, inflammation and fibrosis were evaluated on days 0, 4, 7, 10, 14, 28 and 42. Splenocyte subpopulations were cell sorted and quantitated by FACS. RESULTS: IRF9−/− mice showed dramatically increased mortality compared to the wild-type littermates (0% WT vs 72% IRF-9 −/− on day 14, P<0.0001). On day 42, there was less cardiac hypertrophy and inflammation in IRF-9 −/− mice compared to WT controls (p<0.05). There was no difference in fibrosis. The mature T-lymphocyte population, defined as CD4 or CD8 single positive, was statistically identical in the two populations up until and including day 28 post-infection. However on day 42 there was a dramatic increase in the number of cytotoxic and helper T-Cells in the wild-type mice that was not observed in the IRF-9 −/− spleens (p<0.05). CONCLUSIONS: These data suggest a novel dual role of IRF-9 in not only regulating interferon in acute stage of viral infection in myocarditis, but also late acquired immunity activation, including CD4/8 populations, contributing to the development of chronic cardiomyopathy.

scholarly journals African swine fever virus E120R protein inhibits interferon-β production by interacting with IRF3 to block its activation

2021 ◽  
Author(s):  
Huisheng Liu ◽  
Zixiang Zhu ◽  
Tao Feng ◽  
Zhao Ma ◽  
Qiao Xue ◽  
...  
Keyword(s):  
Type I Interferon ◽  
African Swine Fever Virus ◽  
African Swine Fever ◽  
Interferon Regulatory Factor ◽  
Fever Virus ◽  
Type I ◽  
Interferon Production ◽  
Structural Protein ◽  
Regulatory Factor ◽  
Host Antiviral Response

African swine fever is a devastating disease of swine caused by African swine fever virus (ASFV). The pathogenesis of the disease remains largely unknown, leaving the uncontrolled spreading of the disease in many countries and regions. Here, we identified the E120R, a structural protein of ASFV, as a key virulent factor and late phase expression protein of the virus. E120R revealed an activity to suppress host antiviral response through blocking IFN-β production, and the 72-73 amino acid sites in the C-terminal domain were essential for this function. E120R interacted with the interferon regulatory factor 3 (IRF3) and interfered with the recruitment of IRF3 to TBK1, which in turn suppressed IRF3 phosphorylation, decreasing interferon production. The recombinant mutant ASFV was further constructed to confirm the claimed mechanism. The ASFV lacking the complete E120R region could not be rescued, whereas the virus could tolerate the deletion of the 72nd and 73rd residuals in the E120R (ASFV E120R-Δ72-73aa). ASFV E120R with the two amino acids deletion failed to interact with IRF3 during ASFV E120R-Δ72-73aa infection, and the viral infection highly activated IRF3 phosphorylation and induced more robust type I interferon production in comparison with its parental ASFV. An unbiased transcriptome-wide analysis of gene expression also confirmed that a considerably higher level of ISGs was detected in ASFV E120R-Δ72-73aa-infected porcine alveolar macrophages (PAMs) than that in the wildtype ASFV-infected PAMs. Together, our findings found a novel mechanism evolved by ASFV to inhibit host antiviral response and provide a new target for guiding the development of ASFV live-attenuated vaccine. IMPORTANCE African swine fever is a highly contagious animal disease affecting pig industry worldwide, which has brought enormous economic losses. The causative agent African swine fever virus (ASFV) infection causes severe immunosuppression during viral infection, attributing to serious clinical manifestation. Therefore, identification of the viral proteins involved in immunosuppression is critical for ASFV vaccine design and development. Here, for the first time, we demonstrated that E120R protein, a structural protein of ASFV, played an important role in suppression of interferon regulatory factor 3 (IRF3) phosphorylation and type I interferon production by binding to IRF3 and blocking the the recruitment of IRF3 to TBK1. Deletion of the crucial binding sites in E120R critically increased interferon response during ASFV infection. This study explored a novel antagonistic mechanism of ASFV, which is critical for guiding the development of ASFV live-attenuated vaccines.

scholarly journals DHAV-1 Blocks the Signaling Pathway Upstream of Type I Interferon by Inhibiting the Interferon Regulatory Factor 7 Protein

2021 ◽  
Vol 12 ◽  
Author(s):  
Yalan Lai ◽  
Xiaoyan Xia ◽  
Anchun Cheng ◽  
Mingshu Wang ◽  
Xumin Ou ◽  
...  
Keyword(s):  
Immune Response ◽  
Innate Immunity ◽  
Viral Protein ◽  
Interferon Regulatory Factor ◽  
Host Cells ◽  
Luciferase Reporter ◽  
Type I ◽  
Dependent Manner ◽  
Regulatory Factor ◽  
Interferon Regulatory Factor 7

Duck hepatitis A virus (DHAV), which mainly infects 1- to 4-week-old ducklings, has a fatality rate of 95% and poses a huge economic threat to the duck industry. However, the mechanism by which DHAV-1 regulates the immune response of host cells is rarely reported. This study examined whether DHAV-1 contains a viral protein that can regulate the innate immunity of host cells and its specific regulatory mechanism, further exploring the mechanism by which DHAV-1 resists the host immune response. In the study, the dual-luciferase reporter gene system was used to screen the viral protein that regulates the host innate immunity and the target of this viral protein. The results indicate that the DHAV-1 3C protein inhibits the pathway upstream of interferon (IFN)-β by targeting the interferon regulatory factor 7 (IRF7) protein. In addition, we found that the 3C protein inhibits the nuclear translocation of the IRF7 protein. Further experiments showed that the 3C protein interacts with the IRF7 protein through its N-terminus and that the 3C protein degrades the IRF7 protein in a caspase 3-dependent manner, thereby inhibiting the IFN-β-mediated antiviral response to promote the replication of DHAV-1. The results of this study are expected to serve as a reference for elucidating the mechanisms of DHAV-1 infection and pathogenicity.

scholarly journals Peste des Petits Ruminants Virus Nucleocapsid Protein Inhibits Beta Interferon Production by Interacting with IRF3 To Block Its Activation

2019 ◽  
Vol 93 (16) ◽  
Author(s):  
Zixiang Zhu ◽  
Pengfei Li ◽  
Fan Yang ◽  
Weijun Cao ◽  
Xiangle Zhang ◽  
...  
Keyword(s):  
Nuclear Translocation ◽  
Type I Interferon ◽  
Interferon Regulatory Factor ◽  
Type I ◽  
Peste Des Petits Ruminants ◽  
Type I Ifn ◽  
Regulatory Factor ◽  
N Protein ◽  
Beta Interferon ◽  
Natural Hosts

ABSTRACTPeste des petits ruminants virus (PPRV) is the etiological agent of peste des petits ruminants, causing acute immunosuppression in its natural hosts. However, the molecular mechanisms by which PPRV antagonizes the host immune responses have not been fully characterized. In particular, how PPRV suppresses the activation of the host RIG-I-like receptor (RLR) pathway has yet to be clarified. In this study, we demonstrated that PPRV infection significantly suppresses RLR pathway activation and type I interferon (IFN) production and identified PPRV N protein as an extremely important antagonistic viral factor that suppresses beta interferon (IFN-β) and IFN-stimulated gene (ISG) expression. A detailed analysis showed that PPRV N protein inhibited type I IFN production by targeting interferon regulatory factor 3 (IRF3), a key molecule in the RLR pathway required for type I IFN induction. PPRV N protein interacted with IRF3 (but not with other components of the RLR pathway, including MDA5, RIG-I, VISA, TBK1, and MITA) and abrogated the phosphorylation of IRF3. As expected, PPRV N protein also considerably impaired the nuclear translocation of IRF3. The TBK1-IRF3 interaction was involved significantly in IRF3 phosphorylation, and we showed that PPRV N protein inhibits the association between TBK1 and IRF3, which in turn inhibits IRF3 phosphorylation. The amino acid region 106 to 210 of PPRV N protein was determined to be essential for suppressing the nuclear translocation of IRF3 and IFN-β production, and the 140 to 400 region of IRF3 was identified as the crucial region for the N-IRF3 interaction. Together, our findings demonstrate a new mechanism evolved by PPRV to inhibit type I IFN production and provide structural insights into the immunosuppression caused by PPRV.IMPORTANCEPeste des petits ruminants is a highly contagious animal disease affecting small ruminants, which threatens both small livestock and endangered susceptible wildlife populations in many countries. The causative agent, peste des petits ruminants virus (PPRV), often causes acute immunosuppression in its natural hosts during infection. Here, for the first time, we demonstrate that N protein, the most abundant protein of PPRV, plays an extremely important role in suppression of interferon regulatory factor 3 (IRF3) function and type I interferon (IFN) production by interfering with the formation of the TBK1-IRF3 complex. This study explored a novel antagonistic mechanism of PPRV.

scholarly journals Type I Interferon Production Induced by Streptococcus pyogenes-Derived Nucleic Acids Is Required for Host Protection

2011 ◽  
Vol 7 (5) ◽  
pp. e1001345 ◽  
Author(s):  
Nina Gratz ◽  
Harald Hartweger ◽  
Ulrich Matt ◽  
Franz Kratochvill ◽  
Marton Janos ◽  
...  
Keyword(s):  
Nucleic Acids ◽  
Streptococcus Pyogenes ◽  
Type I Interferon ◽  
Type I ◽  
Interferon Production ◽  
Host Protection
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