Type I interferons are critical antiviral cytokines produced following herpes simplex virus type-1 （HSV-1） infection that act to inhibit viral spread. In the present study, we identify HSV-infected and adjacent unin...Type I interferons are critical antiviral cytokines produced following herpes simplex virus type-1 （HSV-1） infection that act to inhibit viral spread. In the present study, we identify HSV-infected and adjacent uninfected corneal epithelial cells as the source of interferon-a. We also report mice deficient in the A1 chain of the type I IFN receptor （CDl18-/） are extremely sensitive to ocular infection with low doses （100 PFU） of HSV-1 as seen by significantly elevated viral titers in the cornea Compared to wild type （WT） controls. The enhanced susceptibil- ity correlated with a loss of CD4＋ and CD8＋ T cell recruitment and aberrant chemokine production in the cornea despite mounting an adaptive immune response in the draining mandibular lymph node of CDll8/ mice. Taken together, these results highlight the importance of IFN production in both the innate immune response as well as eliciting chemokine production required to facilitate adaptive immune cell trafficking.展开更多
As one of the deadliest viruses,Ebola virus(EBOV)causes lethal hemorrhagic fevers in humans and nonhuman primates.The suppression of innate immunity leads to robust systemic virus replication of EBOV,leading to enhanc...As one of the deadliest viruses,Ebola virus(EBOV)causes lethal hemorrhagic fevers in humans and nonhuman primates.The suppression of innate immunity leads to robust systemic virus replication of EBOV,leading to enhanced transmission.However,the mechanism of EBOV-host interaction is not fully understood.Here,we identified multiple dysregulated genes in early stage of EBOV infection through transcriptomic analysis,which are highly clustered to Jak-STAT signaling.EBOV VP35 and VP30 were found to inhibit type I interferon(IFN)signaling.Moreover,exogenous expression of VP35 blocks the phosphorylation of endogenous STAT1,and suppresses nuclear translocation of STAT1.Using serial truncated mutations of VP35,N-terminal 1–220amino acid residues of VP35 were identified to be essential for blocking on type I IFN signaling.Remarkably,VP35 of EBOV suppresses type I IFN signaling more efficiently than those of Bundibugyo virus(BDBV)and Marburg virus(MARV),resulting in stable replication to facilitate the pathogenesis.Altogether,this study enriches understanding on EBOV evasion of innate immune response,and provides insights into the interplay between filoviruses and host.展开更多
African swine fever(ASF)is originally reported in East Africa as an acute hemorrhagic fever.African swine fever virus(ASFV)is a giant and complex DNA virus with icosahedral structure and encodes a variety of virulence...African swine fever(ASF)is originally reported in East Africa as an acute hemorrhagic fever.African swine fever virus(ASFV)is a giant and complex DNA virus with icosahedral structure and encodes a variety of virulence factors to resist host innate immune response.S273R protein(pS273R),as a SUMO-1 specific cysteine protease,can affect viral packaging by cutting polymeric proteins.In this study,we found that pS273R was an important antagonistic viral factor that suppressed cGAS-STING-mediated type I interferon(IFN-I)production.A detailed analysis showed that pS273R inhibited IFN-I production by interacting with interferon regulatory factor 3(IRF3).Subsequently,we showed that pS273R disrupted the association between TBK1 and IRF3,leading to the repressed IRF3 phosphorylation and dimerization.Deletion and point mutation analysis verified that pS273R impaired IFN-I production independent of its cysteine protease activity.These findings will help us further understand ASFV pathogenesis.展开更多
Interferon regulatory factor 7 plays a crucial role in the innate immune response.However,whether interferon regulatory factor 7-mediated signaling contributes to Parkinson's disease remains unknown.Here we report...Interferon regulatory factor 7 plays a crucial role in the innate immune response.However,whether interferon regulatory factor 7-mediated signaling contributes to Parkinson's disease remains unknown.Here we report that interferon regulatory factor 7 is markedly up-regulated in a 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine-induced mouse model of Parkinson's disease and co-localizes with microglial cells.Both the selective cyclic guanosine monophosphate adenosine monophosphate synthase inhibitor RU.521 and the stimulator of interferon genes inhibitor H151 effectively suppressed interferon regulatory factor 7 activation in BV2 microglia exposed to 1-methyl-4-phenylpyridinium and inhibited transformation of mouse BV2 microglia into the neurotoxic M1 phenotype.In addition,si RNA-mediated knockdown of interferon regulatory factor 7 expression in BV2 microglia reduced the expression of inducible nitric oxide synthase,tumor necrosis factorα,CD16,CD32,and CD86 and increased the expression of the anti-inflammatory markers ARG1 and YM1.Taken together,our findings indicate that the cyclic guanosine monophosphate adenosine monophosphate synthase-stimulator of interferon genes-interferon regulatory factor 7 pathway plays a crucial role in the pathogenesis of Parkinson's disease.展开更多
Background The role of type I interferon(IFN-I)signaling in systemic lupus erythematosus(SLE)has been well established.However,unanswered questions remain regarding the applicability of these findings to pediatric-ons...Background The role of type I interferon(IFN-I)signaling in systemic lupus erythematosus(SLE)has been well established.However,unanswered questions remain regarding the applicability of these findings to pediatric-onset SLE.The aim of this review is to provide an overview of the novel discoveries on IFN-I signaling in pediatric-onset SLE.Data sources A literature search was conducted in the PubMed database using the following keywords:“pediatric systemic lupus erythematosus”and“type I interferon”.Results IFN-I signaling is increased in pediatric SLE,largely due to the presence of plasmacytoid dendritic cells and pathways such as cyclic GMP-AMP synthase–stimulator of interferon genes–TANK-binding kinase 1 and Toll-like receptor(TLR)4/TLR9.Neutrophil extracellular traps and oxidative DNA damage further stimulate IFN-I production.Genetic variants in IFN-I-related genes,such as IFN-regulatory factor 5 and tyrosine kinase 2,are linked to SLE susceptibility in pediatric patients.In addition,type I interferonopathies,characterized by sustained IFN-I activation,can mimic SLE symptoms and are thus important to distinguish.Studies on interferonopathies also contribute to exploring the pathogenesis of SLE.Measuring IFN-I activation is crucial for SLE diagnosis and stratification.Both IFNstimulated gene expression and serum IFN-α2 levels are common indicators.Flow cytometry markers such as CD169 and galectin-9 are promising alternatives.Anti-IFN therapies,such as sifalimumab and anifrolumab,show promise in adult patients with SLE,but their efficacy in pediatric patients requires further investigation.Janus kinase inhibitors are another treatment option for severe pediatric SLE patients.Conclusions This review presents an overview of the IFN-I pathway in pediatric SLE.Understanding the intricate relationship between IFN-I and pediatric SLE may help to identify potential diagnostic markers and targeted therapies,paving the way for improved patient care and outcomes.展开更多
Objective The study aims to investigate the effects of interleukin-2-inducible T-cell kinase(ITK)on hepatitis B virus(HBV)-induced type I interferon(IFN)expression and the antiviral response.Methods Expression of ITK ...Objective The study aims to investigate the effects of interleukin-2-inducible T-cell kinase(ITK)on hepatitis B virus(HBV)-induced type I interferon(IFN)expression and the antiviral response.Methods Expression of ITK and type I interferon(IFN)were examined in peripheral blood mononuclear cells from 20 healthy volunteers and 45 HBV-infected patients.Mouse primary hepatocytes were treated with the ITK inhibitor ibrutinib to assess the expression of type I IFN after HBV infection in vitro.Mice were treated with ibrutinib and evaluated for its effects on HBV infection in vivo.The effects of type I IFN production were explored in cells with an ITK deletion or a double knockout of ITK and suppressor of cytokine signaling 1(SOCS1)engineered via CRISPR.Results The expression levels of ITK and IFN-βwere upregulated in patients with acute HBV infection.HBV-induced expression of type I IFN was effectively inhibited by treatment with ibrutinib.ITK negatively regulated the expression of SOSC1,whereas inhibiting ITK expression decreased IFN regulatory factor 3 activity and increased SOCS1 expression.In the SOCS1 knockout,the downregulated phenotype of type I IFN expression in ITK-deficient cells was reversed after HBV infection.Conclusion ITK regulated HBV-induced expression of type I IFN by modulating SOCS1.展开更多
RIG-I is a pivotal cytoplasmic sensor that recognizes different species of viral RNAs. This recognition leads to activation of the transcription factors NF-κB and IRF3, which collaborate to induce type I interferons ...RIG-I is a pivotal cytoplasmic sensor that recognizes different species of viral RNAs. This recognition leads to activation of the transcription factors NF-κB and IRF3, which collaborate to induce type I interferons （IFNs） and innate antiviral response. In this study, we identified the TRIM family protein TRIM4 as a positive regulator of RIG-I-mediated IFN induction. Overexpression of TRIM4 potentiated virus-triggered activation of IRF3 and NF-κB, as well as IFN-13 induction, whereas knockdown of TRIM4 had opposite effects. Mechanistically, TRIM4 associates with RIG-I and targets it for K63-linked poiyubiquitination. Our findings demonstrate that TRIM4 is an important regulator of the virus-induced IFN induction pathways by mediating RIG-I for K63-Unked ubiquitination.展开更多
Hepatitis B virus(HBV)is regarded as a stealth virus,invading and replicating efficiently in human liver undetected by host innate antiviral immunity.Here,we show that type I interferon(IFN)induction but not its downs...Hepatitis B virus(HBV)is regarded as a stealth virus,invading and replicating efficiently in human liver undetected by host innate antiviral immunity.Here,we show that type I interferon(IFN)induction but not its downstream signaling is blocked by HBV replication in HepG2.2.15 cells.This effect may be partially due to HBV X protein(HBx),which impairs IFNβpromoter activation by both Sendai virus(SeV)and components implicated in signaling by viral sensors.As a deubiquitinating enzyme(DUB),HBx cleaves Lys63-linked polyubiquitin chains from many proteins except TANK-binding kinase 1(TBK1).It binds and deconjugates retinoic acid-inducible gene I(RIG I)and TNF receptor-associated factor 3(TRAF3),causing their dissociation from the downstream adaptor CARDIF or TBK1 kinase.In addition to RIG I and TRAF3,HBx also interacts with CARDIF,TRIF,NEMO,TBK1,inhibitor of kappa light polypeptide gene enhancer in B-cells,kinase epsilon(IKKi)and interferon regulatory factor 3(IRF3).Our data indicate that multiple points of signaling pathways can be targeted by HBx to negatively regulate production of type I IFN.展开更多
Retinoic acid-inducible gene-I(RIG-I)functions as an intracellular pattern recognition receptor(PRR)that recognizes the 5'-triphosphate moiety of single-stranded RNA viruses to initiate the innate immune response....Retinoic acid-inducible gene-I(RIG-I)functions as an intracellular pattern recognition receptor(PRR)that recognizes the 5'-triphosphate moiety of single-stranded RNA viruses to initiate the innate immune response.Previous studies have shown that Lys63-linked ubiquitylation is required for RIG-I activation and the downstream anti-viral type I interferon(IFN-I)induction.Herein we reported that,RIG-I was also modified by small ubiquitin-like modifier-1(SUMO-1).Functional analysis showed that RIG-I SUMOylation enhanced IFN-I production through increased ubiquitylation and the interaction with its downstream adaptor molecule Cardif.Our results therefore suggested that SUMOylation might serve as an additional regulatory tier for RIG-I activation and IFN-I signaling.展开更多
Phosphatase and tensin homolog deleted on chromosome ten(PTEN)is a well-known tumor suppressor that acts as a dual-specificity phosphatase and is frequently mutated in human cancer.Our previous work has demonstrated t...Phosphatase and tensin homolog deleted on chromosome ten(PTEN)is a well-known tumor suppressor that acts as a dual-specificity phosphatase and is frequently mutated in human cancer.Our previous work has demonstrated that PTEN also plays a vital role in type I interferon responses and antiviral innate immunity.Recently,a translational variant of PTEN with a long N-terminal extension(PTEN-L)has been discovered that is secreted into the extracellular environment and enters recipient cells,where it exerts a phosphatase function antagonistic to PI3K/Akt signaling and tumorigenesis.In this study,we demonstrate that PTEN-L promotes type I interferon responses and antiviral innate immunity during viral infection in a phosphatase activity-dependent manner.Compared with canonical PTEN,PTEN-L also exerts its antiviral function when it is applied exogenously in protein form.This finding was confirmed in cell cultures and mouse infection models.Furthermore,PTEN-L enhances the responses of both type I interferon and proinflammatory cytokines,thus suggesting that PTEN-L might possess additional functions compared with those of PTEN.Thus,the antiviral function of PTEN-L may open an avenue for the use of PTEN-L in antiviral therapy,particularly in patients with PTEN-deficient tumors.展开更多
Background and Aims:Hepatocellular carcinoma(HCC)is listed as one of the most common causes of cancer-related death.Oncolytic therapy has become a promising treatment because of novel immunotherapies and gene editing ...Background and Aims:Hepatocellular carcinoma(HCC)is listed as one of the most common causes of cancer-related death.Oncolytic therapy has become a promising treatment because of novel immunotherapies and gene editing technology,but biosafety concerns remain the biggest limitation for clinical application.We studied the the antitumor activity and biosafety of the wild-type Newcastle disease virus HK84 strain(NDV/HK84)and 10 other NDV strains.Meth-ods:Cell proliferation and apoptosis were determined by cell counting Kit-8 and fluorescein isothiocyanate Annexin V apoptosis assays.Colony formation,wound healing,and a xenograft mouse model were used to evaluate in vivo and in vitro oncolytic effectiveness.The safety of NDV/HK84 was tested in nude mice by an in vivo luciferase imaging system.The replication kinetics of NDV/HK84 in normal tis-sues and tumors were evaluated by infectious-dose assays in eggs.RNA sequencing analysis was performed to explore NDV/HK84 activity and was validated by quantitative real-time PCR.Results:The cell counting Kit-8 assays of vi-ability found that the oncolytic activity of the NDV strains differed with the multiplicity of infection(MOI).At an MOI of 20,the oncolytic activity of all NDV strains except the DK/JX/21358/08 strain was>80%.The oncolytic activities of the NDV/HK84 and DK/JX/8224/04 strains were>80%at both MOI=20 and MOI=2.Only NDV/HK84 had>80%oncolytic activities at both MOI=20 and MOI=2.We chose NDV/HK84 as the candidate virus to test the oncolytic effect of NDV in HCC in the in vitro and in vivo experiments.NDV/HK84 killed human SK-HEP-1 HCC cells without affecting healthy cells.Conclusions:Intratumor infection with NDV/HK84 strains compared with vehicle controls or positive controls indicated that NDV/HK84 strain specifically inhib-ited HCC without affecting healthy mice.High-throughput RNA sequencing showed that the oncolytic activity of NDV/HK84 was dependent on the activation of type I interferon signaling.展开更多
COVID-19 is caused by SARS-CoV-2.1 As of July 16th,2020,there were 13,579,581 diagnosed cases and 584,782 deaths attributed to COVID-19 reported globally(https://coronavirus.jhu.edu/map.html).
Pregnancy is a unique immunologic and microbial condition that requires an adequate level of awareness to provide a fast and protective response against pathogens as well as to maintain a state of tolerance to paterna...Pregnancy is a unique immunologic and microbial condition that requires an adequate level of awareness to provide a fast and protective response against pathogens as well as to maintain a state of tolerance to paternal antigens.Dysregulation of inflammatory pathways in the placenta triggered by pathogens is one of the main factors responsible for pregnancy complications.Type I IFNs are key molecules modulating immune responses at the level of the placenta and are crucial for protection of the pregnancy via their antiviral and immune modulatory properties.In this study,we elucidate the mechanisms controlling the basal expression of IFNβand its negative feedback.Using in vitro and in vivo animal models,we found that TLR signaling maintains basal IFNβlevels through the TLR4-MyD88-independent TBK/IRF3 signaling pathway.We describe the role of the TAM receptor Axl in the regulation of IFNβfunction in human and mouse trophoblast cells.The absence of TAM receptors in vivo is associated with fetal demise due to dysregulation of IFNβexpression and its pro-apoptotic downstream effectors.Collectively,our data describe a feedback signaling pathway controlling the expression and function of IFNβin the trophoblast that is essential for an effective response during viral and microbial infections.展开更多
Innate immunity is the first line of host defense against viral infections.Mitochondria,best known as the cell’s“power plant”for ATP generation,have recently been shown to serve as essential platforms for the signa...Innate immunity is the first line of host defense against viral infections.Mitochondria,best known as the cell’s“power plant”for ATP generation,have recently been shown to serve as essential platforms for the signaling events that induce antiviral type I interferon(IFN).Localization of the adaptor mitochondrial antiviral signaling protein(MAVS)to the mitochondrial surface via a Cterminal transmembrane domain is required for RIG-I-like receptors(RLRs)to transduce antiviral signaling upon detection of double-stranded RNA in the cytosol.Mitochondrial quality control through autophagy(i.e.,mitophagy)can impact RLR/MAVS signaling through effects on mitochondrial mass and function.1 Previous studies have generally indicated that mitophagy promotes virus infection by decreasing RLR/MAVS signaling and downstream type I IFN production.2 Viruses can interestingly coopt this housekeeping function for their benefit,as viral proteins translocate to mitochondria,accelerate mitophagy through attenuation of mitochondrial membrane potential,and thereby suppress RIG-I signaling.3 MAVS signaling to type I IFN can also be regulated by mitochondrial dynamics through fusion and fission,whereby MAVS expression promotes fission,while fission inhibits MAVS.4 Finally,type I IFNs have recently themselves been shown to prime antiviral responses in part through reprogramming mitochondrial metabolism,suggesting the existence of complex feedback loops.展开更多
Coronavirus disease 2019(COVID-19)is a multi-system disease that can lead to various severe complications.Acute limb ischemia(ALI)has been increasingly recognized as a COVID-19-associated complication that often predi...Coronavirus disease 2019(COVID-19)is a multi-system disease that can lead to various severe complications.Acute limb ischemia(ALI)has been increasingly recognized as a COVID-19-associated complication that often predicts a poor prognosis.However,the pathophysiology and molecular mechanisms underlying COVID-19-associated ALI remain poorly understood.Hypercoagulability and thrombosis are considered important mechanisms,but we also emphasize the roles of vasospasm,hypoxia,and acidosis in the pathogenesis of the disease.The angiotensin-converting enzyme 2(ACE2)pathway,inflammation,and platelet activation may be important molecular mechanisms underlying these pathological changes induced by COVID-19.Furthermore,we discuss the hypotheses of risk factors for COVID-19-associated ALI from genetic,age,and gender perspectives based on our analysis of molecular mechanisms.Additionally,we summarize therapeutic approaches such as use of the interleukin-6(IL-6)blocker tocilizumab,calcium channel blockers,and angiotensin-converting enzyme inhibitors,providing insights for the future treatment of coronavirus-associated limb ischemic diseases.展开更多
TypeⅠinterferon(IFN)-mediated innate immune responses represent the first line of host defense against viral infection.However,the molecular mechanisms by which avian infuenza virus(AIV)inhibits typeⅠIFN production ...TypeⅠinterferon(IFN)-mediated innate immune responses represent the first line of host defense against viral infection.However,the molecular mechanisms by which avian infuenza virus(AIV)inhibits typeⅠIFN production in ducks are not well understood.Here,we frst found that the polymerase basic 2(PB2)protein of H5N1 subtype AIV inhibited the typeⅠIFN responses by targeting duck mitochondrial antiviral signaling protein(MAVS).We further demonstrated that H5N1-PB2 bound to theΔtransmembrane(ΔTM)domain of duck MAVS,and the polymerase basic 1(PB1)binding domain(PBD)and RNA binding nuclear import domain(RND)of H5N1-PB2 interacted with MAVS to inhibit typeⅠIFN expression in ducks.Collectively,our fndings contribute to understanding the molecular mechanism by which AIV proteins regulate the retinoic acid-inducible geneⅠ(RIG-Ⅰ)-like receptor(RLR)signaling pathway to evade host antiviral immune responses in ducks.展开更多
A number of cytokines are secreted during HIV infection that enhances both innate and adaptive immune responses. Interferon-α/β/γ, IL-12, IL-15 and IL-18 have been found to contribute to the development, maturation...A number of cytokines are secreted during HIV infection that enhances both innate and adaptive immune responses. Interferon-α/β/γ, IL-12, IL-15 and IL-18 have been found to contribute to the development, maturation, differentiation and function of NK and other immune cells. The levels of IFN-α/β/γ, IL-12, IL-15 and IL-18 were compared in the plasma of 90 HIV-1 infected and 90 HIV-2 infected subjects by ELISA or Cytometric Beads Array assays. The HIV-infected subjects were stratified according to CD4<sup>+</sup> T cell counts into three groups: >500, 200 - 500 and <200 cells/ul, with 30 subjects in each group. Cytokine levels were also determined in the plasma of 50 HIV uninfected blood bank donors. Among the cytokines tested, IFN-α was found to be significantly increased in HIV-2 infected compared to HIV-1 infected subjects at high CD4<sup>+</sup> T cell counts (p = 0.001). The levels of IFN-β were seen to differ between the two infections in patients from the category of medium CD4<sup>+</sup> T cell counts: this was significantly increased in HIV-2 infected patients (p < 0.001) as well as compared to uninfected controls (p = 0.001). The levels of IFN-γ were similar at all the CD4<sup>+</sup> T cell categories except for an increase in HIV-2 infected patients at low CD4<sup>+</sup> T cell counts (p = 0.02). The levels of these cytokines were similar in all HIV-1 subjects. Also, the level of IL-12p70 was similar between the two infections but significantly higher in HIV-2 at low compared to medium CD4<sup>+</sup> T cells categories (p = 0.047). Similar to IFN-γ and IL-12p70, the levels of both IL-18 and IL-15 were found to be significantly higher in HIV-2 infected patients compared to HIV-1 at low CD4<sup>+</sup> T cell counts (p < 0.05). These data show that there is variability in the levels of innate cytokines at different stages of HIV infection but the finding of increased IFN-α in HIV-2 infected asymptomatic subjects is consistent with the high innate NK responses previously noted at this stage of infection.展开更多
The intricate interplay between the human immune system and cancer development underscores the central role of immunotherapy in cancer treatment.Within this landscape,the innate immune system,a critical sentinel prote...The intricate interplay between the human immune system and cancer development underscores the central role of immunotherapy in cancer treatment.Within this landscape,the innate immune system,a critical sentinel protecting against tumor incursion,is a key player.The cyclic GMP-AMP synthase(c GAS)and stimulator of interferon genes(STING)pathway has been found to be a linchpin of innate immunity:activation of this signaling pathway orchestrates the production of type I interferon(IFN-α/β),thus fostering the maturation,differentiation,and mobilization of immune effectors in the tumor microenvironment.Furthermore,STING activation facilitates the release and presentation of tumor antigens,and therefore is an attractive target for cancer immunotherapy.Current strategies to activate the STING pathway,including use of pharmacological agonists,have made substantial advancements,particularly when combined with immune checkpoint inhibitors.These approaches have shown promise in preclinical and clinical settings,by enhancing patient survival rates.This review describes the evolving understanding of the c GAS-STING pathway's involvement in tumor biology and therapy.Moreover,this review explores classical and non-classical STING agonists,providing insights into their mechanisms of action and potential for optimizing immunotherapy strategies.Despite challenges and complexities,the c GAS-STING pathway,a promising avenue for enhancing cancer treatment efficacy,has the potential to revolutionize patient outcomes.展开更多
基金supported by USPHS grant (No. AI053108) to DanielJ.J. CarrP20 (No. RR017703)+1 种基金an unrestricted grant from Research to Prevent Blindnesssupported by NIAID training grant(No. AI007633)
文摘Type I interferons are critical antiviral cytokines produced following herpes simplex virus type-1 （HSV-1） infection that act to inhibit viral spread. In the present study, we identify HSV-infected and adjacent uninfected corneal epithelial cells as the source of interferon-a. We also report mice deficient in the A1 chain of the type I IFN receptor （CDl18-/） are extremely sensitive to ocular infection with low doses （100 PFU） of HSV-1 as seen by significantly elevated viral titers in the cornea Compared to wild type （WT） controls. The enhanced susceptibil- ity correlated with a loss of CD4＋ and CD8＋ T cell recruitment and aberrant chemokine production in the cornea despite mounting an adaptive immune response in the draining mandibular lymph node of CDll8/ mice. Taken together, these results highlight the importance of IFN production in both the innate immune response as well as eliciting chemokine production required to facilitate adaptive immune cell trafficking.
基金the Strategic Priority Research Program of the Chinese Academy of Sciences(Grant No.XDB0490000)the National Natural Science Foundation of China(82202521).
文摘As one of the deadliest viruses,Ebola virus(EBOV)causes lethal hemorrhagic fevers in humans and nonhuman primates.The suppression of innate immunity leads to robust systemic virus replication of EBOV,leading to enhanced transmission.However,the mechanism of EBOV-host interaction is not fully understood.Here,we identified multiple dysregulated genes in early stage of EBOV infection through transcriptomic analysis,which are highly clustered to Jak-STAT signaling.EBOV VP35 and VP30 were found to inhibit type I interferon(IFN)signaling.Moreover,exogenous expression of VP35 blocks the phosphorylation of endogenous STAT1,and suppresses nuclear translocation of STAT1.Using serial truncated mutations of VP35,N-terminal 1–220amino acid residues of VP35 were identified to be essential for blocking on type I IFN signaling.Remarkably,VP35 of EBOV suppresses type I IFN signaling more efficiently than those of Bundibugyo virus(BDBV)and Marburg virus(MARV),resulting in stable replication to facilitate the pathogenesis.Altogether,this study enriches understanding on EBOV evasion of innate immune response,and provides insights into the interplay between filoviruses and host.
基金the National Natural Science Foundation of China(Grant No.32172869),China.
文摘African swine fever(ASF)is originally reported in East Africa as an acute hemorrhagic fever.African swine fever virus(ASFV)is a giant and complex DNA virus with icosahedral structure and encodes a variety of virulence factors to resist host innate immune response.S273R protein(pS273R),as a SUMO-1 specific cysteine protease,can affect viral packaging by cutting polymeric proteins.In this study,we found that pS273R was an important antagonistic viral factor that suppressed cGAS-STING-mediated type I interferon(IFN-I)production.A detailed analysis showed that pS273R inhibited IFN-I production by interacting with interferon regulatory factor 3(IRF3).Subsequently,we showed that pS273R disrupted the association between TBK1 and IRF3,leading to the repressed IRF3 phosphorylation and dimerization.Deletion and point mutation analysis verified that pS273R impaired IFN-I production independent of its cysteine protease activity.These findings will help us further understand ASFV pathogenesis.
基金supported by the National Natural Science Foundation of China,Nos.82171429,81771384a grant from Wuxi Municipal Health Commission,No.1286010241190480(all to YS)。
文摘Interferon regulatory factor 7 plays a crucial role in the innate immune response.However,whether interferon regulatory factor 7-mediated signaling contributes to Parkinson's disease remains unknown.Here we report that interferon regulatory factor 7 is markedly up-regulated in a 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine-induced mouse model of Parkinson's disease and co-localizes with microglial cells.Both the selective cyclic guanosine monophosphate adenosine monophosphate synthase inhibitor RU.521 and the stimulator of interferon genes inhibitor H151 effectively suppressed interferon regulatory factor 7 activation in BV2 microglia exposed to 1-methyl-4-phenylpyridinium and inhibited transformation of mouse BV2 microglia into the neurotoxic M1 phenotype.In addition,si RNA-mediated knockdown of interferon regulatory factor 7 expression in BV2 microglia reduced the expression of inducible nitric oxide synthase,tumor necrosis factorα,CD16,CD32,and CD86 and increased the expression of the anti-inflammatory markers ARG1 and YM1.Taken together,our findings indicate that the cyclic guanosine monophosphate adenosine monophosphate synthase-stimulator of interferon genes-interferon regulatory factor 7 pathway plays a crucial role in the pathogenesis of Parkinson's disease.
基金supported by National Key Research and Development Program of China(2021YFC2702005)National High level Hospital Clinical Research Foundation(2022-PUMCH-B-079).
文摘Background The role of type I interferon(IFN-I)signaling in systemic lupus erythematosus(SLE)has been well established.However,unanswered questions remain regarding the applicability of these findings to pediatric-onset SLE.The aim of this review is to provide an overview of the novel discoveries on IFN-I signaling in pediatric-onset SLE.Data sources A literature search was conducted in the PubMed database using the following keywords:“pediatric systemic lupus erythematosus”and“type I interferon”.Results IFN-I signaling is increased in pediatric SLE,largely due to the presence of plasmacytoid dendritic cells and pathways such as cyclic GMP-AMP synthase–stimulator of interferon genes–TANK-binding kinase 1 and Toll-like receptor(TLR)4/TLR9.Neutrophil extracellular traps and oxidative DNA damage further stimulate IFN-I production.Genetic variants in IFN-I-related genes,such as IFN-regulatory factor 5 and tyrosine kinase 2,are linked to SLE susceptibility in pediatric patients.In addition,type I interferonopathies,characterized by sustained IFN-I activation,can mimic SLE symptoms and are thus important to distinguish.Studies on interferonopathies also contribute to exploring the pathogenesis of SLE.Measuring IFN-I activation is crucial for SLE diagnosis and stratification.Both IFNstimulated gene expression and serum IFN-α2 levels are common indicators.Flow cytometry markers such as CD169 and galectin-9 are promising alternatives.Anti-IFN therapies,such as sifalimumab and anifrolumab,show promise in adult patients with SLE,but their efficacy in pediatric patients requires further investigation.Janus kinase inhibitors are another treatment option for severe pediatric SLE patients.Conclusions This review presents an overview of the IFN-I pathway in pediatric SLE.Understanding the intricate relationship between IFN-I and pediatric SLE may help to identify potential diagnostic markers and targeted therapies,paving the way for improved patient care and outcomes.
基金supported by Quanzhou City Science&Technology Program of China 455(2022NS056)the Science and Technology Department of Fujian Province(No.2024J01121794).
文摘Objective The study aims to investigate the effects of interleukin-2-inducible T-cell kinase(ITK)on hepatitis B virus(HBV)-induced type I interferon(IFN)expression and the antiviral response.Methods Expression of ITK and type I interferon(IFN)were examined in peripheral blood mononuclear cells from 20 healthy volunteers and 45 HBV-infected patients.Mouse primary hepatocytes were treated with the ITK inhibitor ibrutinib to assess the expression of type I IFN after HBV infection in vitro.Mice were treated with ibrutinib and evaluated for its effects on HBV infection in vivo.The effects of type I IFN production were explored in cells with an ITK deletion or a double knockout of ITK and suppressor of cytokine signaling 1(SOCS1)engineered via CRISPR.Results The expression levels of ITK and IFN-βwere upregulated in patients with acute HBV infection.HBV-induced expression of type I IFN was effectively inhibited by treatment with ibrutinib.ITK negatively regulated the expression of SOSC1,whereas inhibiting ITK expression decreased IFN regulatory factor 3 activity and increased SOCS1 expression.In the SOCS1 knockout,the downregulated phenotype of type I IFN expression in ITK-deficient cells was reversed after HBV infection.Conclusion ITK regulated HBV-induced expression of type I IFN by modulating SOCS1.
基金Funding This work was supported by grants from the Ministry of Science and Technology of China （2012CB910201 and 2010CB911802） and the National Natural Science Foundation of China （31221061, 31130020, and 91029302）.
文摘RIG-I is a pivotal cytoplasmic sensor that recognizes different species of viral RNAs. This recognition leads to activation of the transcription factors NF-κB and IRF3, which collaborate to induce type I interferons （IFNs） and innate antiviral response. In this study, we identified the TRIM family protein TRIM4 as a positive regulator of RIG-I-mediated IFN induction. Overexpression of TRIM4 potentiated virus-triggered activation of IRF3 and NF-κB, as well as IFN-13 induction, whereas knockdown of TRIM4 had opposite effects. Mechanistically, TRIM4 associates with RIG-I and targets it for K63-linked poiyubiquitination. Our findings demonstrate that TRIM4 is an important regulator of the virus-induced IFN induction pathways by mediating RIG-I for K63-Unked ubiquitination.
文摘Hepatitis B virus(HBV)is regarded as a stealth virus,invading and replicating efficiently in human liver undetected by host innate antiviral immunity.Here,we show that type I interferon(IFN)induction but not its downstream signaling is blocked by HBV replication in HepG2.2.15 cells.This effect may be partially due to HBV X protein(HBx),which impairs IFNβpromoter activation by both Sendai virus(SeV)and components implicated in signaling by viral sensors.As a deubiquitinating enzyme(DUB),HBx cleaves Lys63-linked polyubiquitin chains from many proteins except TANK-binding kinase 1(TBK1).It binds and deconjugates retinoic acid-inducible gene I(RIG I)and TNF receptor-associated factor 3(TRAF3),causing their dissociation from the downstream adaptor CARDIF or TBK1 kinase.In addition to RIG I and TRAF3,HBx also interacts with CARDIF,TRIF,NEMO,TBK1,inhibitor of kappa light polypeptide gene enhancer in B-cells,kinase epsilon(IKKi)and interferon regulatory factor 3(IRF3).Our data indicate that multiple points of signaling pathways can be targeted by HBx to negatively regulate production of type I IFN.
基金grants from Chinese Academy of Sciences(Grant No.KSCX1-YW-10)the Ministry of Science and Technology(Grant Nos.2006CB910901,2007DFC30190,2008ZX10001-002 and 2009CB522506)H.T.The authors have no conflicting financial interests.
文摘Retinoic acid-inducible gene-I(RIG-I)functions as an intracellular pattern recognition receptor(PRR)that recognizes the 5'-triphosphate moiety of single-stranded RNA viruses to initiate the innate immune response.Previous studies have shown that Lys63-linked ubiquitylation is required for RIG-I activation and the downstream anti-viral type I interferon(IFN-I)induction.Herein we reported that,RIG-I was also modified by small ubiquitin-like modifier-1(SUMO-1).Functional analysis showed that RIG-I SUMOylation enhanced IFN-I production through increased ubiquitylation and the interaction with its downstream adaptor molecule Cardif.Our results therefore suggested that SUMOylation might serve as an additional regulatory tier for RIG-I activation and IFN-I signaling.
基金We thank Dr Hong Wu for providing Pten−/−MEFs and Dr Hongliang Li for Ptenflox/flox mice and Dr Mingzhou Chen for providing VSV as a gift.This work was supported by the National Nature Science Foundation of China(grant 81620108020)the China‘973’Basic Research Program(#2013CB911101)Hubei Provincial Science&Technology Innovation Team grant(#2015CFA009).
文摘Phosphatase and tensin homolog deleted on chromosome ten(PTEN)is a well-known tumor suppressor that acts as a dual-specificity phosphatase and is frequently mutated in human cancer.Our previous work has demonstrated that PTEN also plays a vital role in type I interferon responses and antiviral innate immunity.Recently,a translational variant of PTEN with a long N-terminal extension(PTEN-L)has been discovered that is secreted into the extracellular environment and enters recipient cells,where it exerts a phosphatase function antagonistic to PI3K/Akt signaling and tumorigenesis.In this study,we demonstrate that PTEN-L promotes type I interferon responses and antiviral innate immunity during viral infection in a phosphatase activity-dependent manner.Compared with canonical PTEN,PTEN-L also exerts its antiviral function when it is applied exogenously in protein form.This finding was confirmed in cell cultures and mouse infection models.Furthermore,PTEN-L enhances the responses of both type I interferon and proinflammatory cytokines,thus suggesting that PTEN-L might possess additional functions compared with those of PTEN.Thus,the antiviral function of PTEN-L may open an avenue for the use of PTEN-L in antiviral therapy,particularly in patients with PTEN-deficient tumors.
基金supported by research grants from the Guangdong Science and Technology Innovation Strategy Special Found(2019B121205009)the Guangdong Science and Technology Special Found(190830095586328 and 200109155890863)and the Li Ka Shing Foundation.
文摘Background and Aims:Hepatocellular carcinoma(HCC)is listed as one of the most common causes of cancer-related death.Oncolytic therapy has become a promising treatment because of novel immunotherapies and gene editing technology,but biosafety concerns remain the biggest limitation for clinical application.We studied the the antitumor activity and biosafety of the wild-type Newcastle disease virus HK84 strain(NDV/HK84)and 10 other NDV strains.Meth-ods:Cell proliferation and apoptosis were determined by cell counting Kit-8 and fluorescein isothiocyanate Annexin V apoptosis assays.Colony formation,wound healing,and a xenograft mouse model were used to evaluate in vivo and in vitro oncolytic effectiveness.The safety of NDV/HK84 was tested in nude mice by an in vivo luciferase imaging system.The replication kinetics of NDV/HK84 in normal tis-sues and tumors were evaluated by infectious-dose assays in eggs.RNA sequencing analysis was performed to explore NDV/HK84 activity and was validated by quantitative real-time PCR.Results:The cell counting Kit-8 assays of vi-ability found that the oncolytic activity of the NDV strains differed with the multiplicity of infection(MOI).At an MOI of 20,the oncolytic activity of all NDV strains except the DK/JX/21358/08 strain was>80%.The oncolytic activities of the NDV/HK84 and DK/JX/8224/04 strains were>80%at both MOI=20 and MOI=2.Only NDV/HK84 had>80%oncolytic activities at both MOI=20 and MOI=2.We chose NDV/HK84 as the candidate virus to test the oncolytic effect of NDV in HCC in the in vitro and in vivo experiments.NDV/HK84 killed human SK-HEP-1 HCC cells without affecting healthy cells.Conclusions:Intratumor infection with NDV/HK84 strains compared with vehicle controls or positive controls indicated that NDV/HK84 strain specifically inhib-ited HCC without affecting healthy mice.High-throughput RNA sequencing showed that the oncolytic activity of NDV/HK84 was dependent on the activation of type I interferon signaling.
基金supported by National Natural Science Foundation of China(No.31900112,21907065,31970130,and 31670831)supported by the National Key Research and Development Program of China Grant(No.2016YFA0500600).
文摘COVID-19 is caused by SARS-CoV-2.1 As of July 16th,2020,there were 13,579,581 diagnosed cases and 584,782 deaths attributed to COVID-19 reported globally(https://coronavirus.jhu.edu/map.html).
基金This study is in part funded by grants P01HD054713,R56AI124356,and 3N01 HD23342 from the Eunice Kennedy Shriver National Institute of Child Health and Human Development,National Institutes of Health,Department of Health and Human Services.
文摘Pregnancy is a unique immunologic and microbial condition that requires an adequate level of awareness to provide a fast and protective response against pathogens as well as to maintain a state of tolerance to paternal antigens.Dysregulation of inflammatory pathways in the placenta triggered by pathogens is one of the main factors responsible for pregnancy complications.Type I IFNs are key molecules modulating immune responses at the level of the placenta and are crucial for protection of the pregnancy via their antiviral and immune modulatory properties.In this study,we elucidate the mechanisms controlling the basal expression of IFNβand its negative feedback.Using in vitro and in vivo animal models,we found that TLR signaling maintains basal IFNβlevels through the TLR4-MyD88-independent TBK/IRF3 signaling pathway.We describe the role of the TAM receptor Axl in the regulation of IFNβfunction in human and mouse trophoblast cells.The absence of TAM receptors in vivo is associated with fetal demise due to dysregulation of IFNβexpression and its pro-apoptotic downstream effectors.Collectively,our data describe a feedback signaling pathway controlling the expression and function of IFNβin the trophoblast that is essential for an effective response during viral and microbial infections.
基金supported by the Intramural Research Program of the National Institute of Environmental Health Sciences(Z01 ES102005),National Institutes of Health.
文摘Innate immunity is the first line of host defense against viral infections.Mitochondria,best known as the cell’s“power plant”for ATP generation,have recently been shown to serve as essential platforms for the signaling events that induce antiviral type I interferon(IFN).Localization of the adaptor mitochondrial antiviral signaling protein(MAVS)to the mitochondrial surface via a Cterminal transmembrane domain is required for RIG-I-like receptors(RLRs)to transduce antiviral signaling upon detection of double-stranded RNA in the cytosol.Mitochondrial quality control through autophagy(i.e.,mitophagy)can impact RLR/MAVS signaling through effects on mitochondrial mass and function.1 Previous studies have generally indicated that mitophagy promotes virus infection by decreasing RLR/MAVS signaling and downstream type I IFN production.2 Viruses can interestingly coopt this housekeeping function for their benefit,as viral proteins translocate to mitochondria,accelerate mitophagy through attenuation of mitochondrial membrane potential,and thereby suppress RIG-I signaling.3 MAVS signaling to type I IFN can also be regulated by mitochondrial dynamics through fusion and fission,whereby MAVS expression promotes fission,while fission inhibits MAVS.4 Finally,type I IFNs have recently themselves been shown to prime antiviral responses in part through reprogramming mitochondrial metabolism,suggesting the existence of complex feedback loops.
基金supported by the Zhejiang Provincial Medical Scientific Research Program(No.2022RC136),China.
文摘Coronavirus disease 2019(COVID-19)is a multi-system disease that can lead to various severe complications.Acute limb ischemia(ALI)has been increasingly recognized as a COVID-19-associated complication that often predicts a poor prognosis.However,the pathophysiology and molecular mechanisms underlying COVID-19-associated ALI remain poorly understood.Hypercoagulability and thrombosis are considered important mechanisms,but we also emphasize the roles of vasospasm,hypoxia,and acidosis in the pathogenesis of the disease.The angiotensin-converting enzyme 2(ACE2)pathway,inflammation,and platelet activation may be important molecular mechanisms underlying these pathological changes induced by COVID-19.Furthermore,we discuss the hypotheses of risk factors for COVID-19-associated ALI from genetic,age,and gender perspectives based on our analysis of molecular mechanisms.Additionally,we summarize therapeutic approaches such as use of the interleukin-6(IL-6)blocker tocilizumab,calcium channel blockers,and angiotensin-converting enzyme inhibitors,providing insights for the future treatment of coronavirus-associated limb ischemic diseases.
基金supported by the grants from the National Natural Science Foundation of China(31872497 and 32072844)the National Key Research and Development Program of China(2021YFD1800200 and 2016YFD0500207)the Laboratory of Lingnan Modern Agriculture Project,China(NT2021007)。
文摘TypeⅠinterferon(IFN)-mediated innate immune responses represent the first line of host defense against viral infection.However,the molecular mechanisms by which avian infuenza virus(AIV)inhibits typeⅠIFN production in ducks are not well understood.Here,we frst found that the polymerase basic 2(PB2)protein of H5N1 subtype AIV inhibited the typeⅠIFN responses by targeting duck mitochondrial antiviral signaling protein(MAVS).We further demonstrated that H5N1-PB2 bound to theΔtransmembrane(ΔTM)domain of duck MAVS,and the polymerase basic 1(PB1)binding domain(PBD)and RNA binding nuclear import domain(RND)of H5N1-PB2 interacted with MAVS to inhibit typeⅠIFN expression in ducks.Collectively,our fndings contribute to understanding the molecular mechanism by which AIV proteins regulate the retinoic acid-inducible geneⅠ(RIG-Ⅰ)-like receptor(RLR)signaling pathway to evade host antiviral immune responses in ducks.
文摘A number of cytokines are secreted during HIV infection that enhances both innate and adaptive immune responses. Interferon-α/β/γ, IL-12, IL-15 and IL-18 have been found to contribute to the development, maturation, differentiation and function of NK and other immune cells. The levels of IFN-α/β/γ, IL-12, IL-15 and IL-18 were compared in the plasma of 90 HIV-1 infected and 90 HIV-2 infected subjects by ELISA or Cytometric Beads Array assays. The HIV-infected subjects were stratified according to CD4<sup>+</sup> T cell counts into three groups: >500, 200 - 500 and <200 cells/ul, with 30 subjects in each group. Cytokine levels were also determined in the plasma of 50 HIV uninfected blood bank donors. Among the cytokines tested, IFN-α was found to be significantly increased in HIV-2 infected compared to HIV-1 infected subjects at high CD4<sup>+</sup> T cell counts (p = 0.001). The levels of IFN-β were seen to differ between the two infections in patients from the category of medium CD4<sup>+</sup> T cell counts: this was significantly increased in HIV-2 infected patients (p < 0.001) as well as compared to uninfected controls (p = 0.001). The levels of IFN-γ were similar at all the CD4<sup>+</sup> T cell categories except for an increase in HIV-2 infected patients at low CD4<sup>+</sup> T cell counts (p = 0.02). The levels of these cytokines were similar in all HIV-1 subjects. Also, the level of IL-12p70 was similar between the two infections but significantly higher in HIV-2 at low compared to medium CD4<sup>+</sup> T cells categories (p = 0.047). Similar to IFN-γ and IL-12p70, the levels of both IL-18 and IL-15 were found to be significantly higher in HIV-2 infected patients compared to HIV-1 at low CD4<sup>+</sup> T cell counts (p < 0.05). These data show that there is variability in the levels of innate cytokines at different stages of HIV infection but the finding of increased IFN-α in HIV-2 infected asymptomatic subjects is consistent with the high innate NK responses previously noted at this stage of infection.
基金the National Key Research and Development Program of China(Grant Nos.2022YFC3401500 and 2020YFA0803201 to P.W.,and 2021YFA1302200 to L.F.)the National Natural Science Foundation of China(Grant Nos.31830053,31920103007,and 82341028 to P.W.+1 种基金82122056,82073153,and 31871398 to L.F.and 31900568 to P.W.)the Natural Science Foundation of Shanghai(Grant No.22ZR1450700 to Z.J.W.)。
文摘The intricate interplay between the human immune system and cancer development underscores the central role of immunotherapy in cancer treatment.Within this landscape,the innate immune system,a critical sentinel protecting against tumor incursion,is a key player.The cyclic GMP-AMP synthase(c GAS)and stimulator of interferon genes(STING)pathway has been found to be a linchpin of innate immunity:activation of this signaling pathway orchestrates the production of type I interferon(IFN-α/β),thus fostering the maturation,differentiation,and mobilization of immune effectors in the tumor microenvironment.Furthermore,STING activation facilitates the release and presentation of tumor antigens,and therefore is an attractive target for cancer immunotherapy.Current strategies to activate the STING pathway,including use of pharmacological agonists,have made substantial advancements,particularly when combined with immune checkpoint inhibitors.These approaches have shown promise in preclinical and clinical settings,by enhancing patient survival rates.This review describes the evolving understanding of the c GAS-STING pathway's involvement in tumor biology and therapy.Moreover,this review explores classical and non-classical STING agonists,providing insights into their mechanisms of action and potential for optimizing immunotherapy strategies.Despite challenges and complexities,the c GAS-STING pathway,a promising avenue for enhancing cancer treatment efficacy,has the potential to revolutionize patient outcomes.
