An overly exuberant immune response,characterized by a cytokine storm and uncontrolled inflammation,has been identified as a significant driver of severe coronavirus disease 2019(COVID-19)cases.Consequently,decipherin...An overly exuberant immune response,characterized by a cytokine storm and uncontrolled inflammation,has been identified as a significant driver of severe coronavirus disease 2019(COVID-19)cases.Consequently,deciphering the intricacies of immune dysregulation in COVID-19 is imperative to identify specific targets for intervention and modulation.With these delicate dynamics in mind,immunomodulatory therapies have emerged as a promising avenue for miti-gating the challenges posed by COVID-19.Precision in manipulating immune pathways presents an opportunity to alter the host response,optimizing antiviral defenses while curbing deleterious inflammation.This review article compre-hensively analyzes immunomodulatory interventions in managing COVID-19.We explore diverse approaches to mitigating the hyperactive immune response and its impact,from corticosteroids and non-steroidal drugs to targeted biologics,including anti-viral drugs,cytokine inhibitors,JAK inhibitors,convalescent plasma,monoclonal antibodies(mAbs)to severe acute respiratory syndrome coronavirus 2,cell-based therapies(i.e.,CAR T,etc.).By summarizing the current evidence,we aim to provide a clear roadmap for clinicians and researchers navigating the complex landscape of immunomodulation in COVID-19 treatment.CS Glucocorticoids are among the most widely prescribed drugs with their immune-suppressive and anti-inflammatory effect[84].The current guidelines for the treatment of COVID-19 recommend against the use of dexamethasone or other systemic CS in non-hospitalized patients in the absence of another indication[70].The RECOVERY trial demonstrates the reduced 28-d mortality among hospitalized patients with COVID-19 using dexamethasone compared to the usual standard of care,along with other investigators,such as Ahmed and Hassan[85].The benefit of dexamethasone was seen only among participants receiving either oxygen alone or invasive mechanical ventilation at randomization but not among those receiving no respiratory support at enrollment[85].In a systematic review and meta-analysis,Albuquerque et al[86]showed that in comparison to tocilizumab,baricitinib,and sarilumab are associated with high probabilities of similar mortality reductions among hospitalized COVID-19 concurrently treated with CS.As a result of the absence of SARS-CoV-2-specific antiviral medications,the effectiveness of COVID-19 treatments is reduced.Several COVID-19 therapies are now under investigation.However,the majority of them lack specificity,efficacy,and safety[87].Immunotherapy is a ground-breaking medical treatment that manipulates the immune system to fight diseases.Translational research is rapidly progressing,recognized as a significant breakthrough in 2013[88].Among the immunotherapeutic options for treating COVID-19 are Immunoglobulin,CP,antibodies,mAbs(mAbs),NK cells,T cells,TLR,cytokine therapies and immune modulators.展开更多
Subject Code:H19With the support by the National Natural Science Foundation of China,a collaborative study by the research groups led by Prof.Zhou Xi(周溪)from the State Key Laboratory of Virology,Wuhan Institute of V...Subject Code:H19With the support by the National Natural Science Foundation of China,a collaborative study by the research groups led by Prof.Zhou Xi(周溪)from the State Key Laboratory of Virology,Wuhan Institute of Virology,Chinese Academy of Sciences and Prof.Qin Chengfeng(秦成峰)from Beijing Institute展开更多
The Janus kinase/signal transducers and activators of transcription(JAK/STAT)signaling pathway play a pivotal role in innate immunity.Among invertebrates,Domeless receptors serve as the key upstream regulators of this...The Janus kinase/signal transducers and activators of transcription(JAK/STAT)signaling pathway play a pivotal role in innate immunity.Among invertebrates,Domeless receptors serve as the key upstream regulators of this pathway.In our study on Bactrocera dorsalis,we identified three cytokine receptors:BdDomeless1,BdDomeless2,and BdDomeless3.Each receptor encompasses five fibronectin-type-III-like(FN III)extracellular domains and a transmembrane domain.Furthermore,these receptors exhibit the increased responsiveness to diverse pathogenic challenges.Notably,only BdDomeless3 is upregulated during symbiont-like viral infections.Moreover,silencing BdDomeless3 enhanced the infectivity of Bactrocera dorsalis cripavirus(BdCV)and B.dorsalis picorna-like virus(BdPLV),underscoring BdDomeless3’s crucial role in antiviral defense of B.dorsalis.Following the suppression of Domeless3 expression,six antimicrobial peptide genes displayed decreased expression,potentially correlating with the rise in viral infectivity.To our knowledge,this is the first study identifying cytokine receptors associated with the JAK/STAT pathway in tephritid flies,shedding light on the immune mechanisms of B.dorsalis.展开更多
The COVID-19 pandemic has revealed sex-based differences in anti-viral responses,with a higher rate of SARS-CoV-2 infections as well as a higher rate of morbidity and mortality in men than in women.Males and females a...The COVID-19 pandemic has revealed sex-based differences in anti-viral responses,with a higher rate of SARS-CoV-2 infections as well as a higher rate of morbidity and mortality in men than in women.Males and females also show disparate immune responses to COVID-19 infection,which may be important contributors to lower rates of infection,disease severity and deaths in women than in men.Here,the authors review sex differences in SARS-CoV-2 infections,anti-viral immunity and vaccine responses,putting forth the importance of sex,the underappreciated variables in vaccine response and disease infectivity.展开更多
Autophagy plays important roles in modulating viral replication and antiviral immune response. Coronavirus infection is associated with the autophagic process, however, little is known about the mechanisms of autophag...Autophagy plays important roles in modulating viral replication and antiviral immune response. Coronavirus infection is associated with the autophagic process, however, little is known about the mechanisms of autophagy induction and its contribution to coronavirus regulation of host innate responses. Here, we show that the membrane-associated papain-like protease PLP2 (PLP2-TM) of coronaviruses acts as a novel autophagy- inducing protein. Intriguingly, PLP2-TM induces incom- plete autophagy process by increasing the accumula- tion of autophagosomes but blocking the fusion of autophagosomes with lysosomes. Furthermore, PLP2- TM interacts with the key autophagy regulators, LC3 and Beclinl, and promotes Beclinl interaction with STING, the key regulator for antiviral IFN signaling. Finally, knockdown of Beclinl partially reverses PLP2-TM's inhibitory effect on innate immunity which resulting in decreased coronavirus replication. These results sug- gested that coronavirus papain-like protease induces incomplete autophagy by interacting with Beclinl, which in turn modulates coronavirus replication and antiviral innate immunity.展开更多
Toll-like receptors(TLRs) are the critical superfamily homologues that initiate sensing of the invasion of pathogens by the Toll pathway. As one of several intracellular nucleic acid-sensing TLRs, TLR13 is activated b...Toll-like receptors(TLRs) are the critical superfamily homologues that initiate sensing of the invasion of pathogens by the Toll pathway. As one of several intracellular nucleic acid-sensing TLRs, TLR13 is activated by an unmethylated motif present in the large ribosomal subunit of bacterial RNA. However, little attention has been paid to the function of TLR13 gene homologue from Laodelphax striatellus(designated as LsToll-13) in the immune response to rice stripe virus(RSV). Herein, LsToll-13 was cloned and characterized using RACE-PCR. Phylogenetic analysis showed that LsToll-13 was clustered with the TLR13 from six insects. Real-time PCR analysis demonstrated that the expression level of LsToll-13 was significantly reduced in L. striatellus with RSV infection compared with that in the naive strain. When the expression of LsToll-13 was significantly up-regulated at 6 h after bacterial infection, the expression of ribonucleoprotein(RNP) indicated that the RSV titer in the host insect was significantly suppressed. Upon knockdown of LsToll-13, using RNA interference(RNAi) in L. striatellus, the expression level of RNP was significantly increased with enhanced RSV accumulation, suggesting that LsToll-13 potentially protects L. striatellus from RSV infection. Taken together, our results indicated that LsToll-13 might be involved in the immune response of L. striatellus to RSV infection, and provided a new insight into further elucidating the molecular mechanisms of complex pathogen-host interactions and integrative pest management.展开更多
Stimulator of interferon genes(STING)is an adaptor protein that is critical for effective innate antiviral and antitumor immunity.The activity of STING is heavily regulated by protein ubiquitination,which is fine-tune...Stimulator of interferon genes(STING)is an adaptor protein that is critical for effective innate antiviral and antitumor immunity.The activity of STING is heavily regulated by protein ubiquitination,which is fine-tuned by both E3 ubiquitin ligases and deubiquitinases.Here,we report that the deubiquitinase OTUD5 interacts with STING,cleaves its K48-linked polyubiquitin chains,and promotes its stability.Consistently,knockout of OTUD5 resulted in faster turnover of STING and subsequently impaired type I IFN signaling following cytosolic DNA stimulation.More importantly,Lyz2-Cre Otud5^(fl/Y) mice and CD11-Cre Otud5^(fl/Y) mice showed more susceptibility to herpes simplex virus type 1(HSV-1)infection and faster development of melanomas than their corresponding control littermates,indicating that OTUD5 is indispensable for STING-mediated antiviral and antitumor immunity.Our data suggest that OTUD5 is a novel checkpoint in the cGAS-STING cytosolic DNA sensing pathway.展开更多
Infection with severe acute respiratory syndrome coronavirus 2(SARS-CoV-2) causes diverse clinical manifestations and tissue injuries in multiple organs.However, cellular and molecular understanding of SARS-CoV-2 infe...Infection with severe acute respiratory syndrome coronavirus 2(SARS-CoV-2) causes diverse clinical manifestations and tissue injuries in multiple organs.However, cellular and molecular understanding of SARS-CoV-2 infection-associated pathology and immune defense features in different organs remains incomplete. Here, we profiled approximately 77 000single-nucleus transcriptomes of the lung, liver,kidney, and cerebral cortex in rhesus macaques(Macaca mulatta) infected with SARS-CoV-2 and healthy controls. Integrated analysis of the multiorgan dataset suggested that the liver harbored the strongest global transcriptional alterations. We observed prominent impairment in lung epithelial cells, especially in AT2 and ciliated cells, and evident signs of fibrosis in fibroblasts. These lung injury characteristics are similar to those reported in patients with coronavirus disease 2019(COVID-19).Furthermore, we found suppressed MHC class I/II molecular activity in the lung, inflammatory response in the liver, and activation of the kynurenine pathway,which induced the development of an immunosuppressive microenvironment. Analysis of the kidney dataset highlighted tropism of tubule cells to SARS-CoV-2, and we found membranous nephropathy(an autoimmune disease) caused by podocyte dysregulation. In addition, we identified the pathological states of astrocytes and oligodendrocytes in the cerebral cortex, providing molecular insights into COVID-19-related neurological implications. Overall, our multi-organ single-nucleus transcriptomic survey of SARS-CoV-2-infected rhesus macaques broadens our understanding of disease features and antiviral immune defects caused by SARS-CoV-2 infection,which may facilitate the development of therapeutic interventions for COVID-19.展开更多
Protein arginine methyltransferases(PRMTs)play diverse biological roles and are specifically involved in immune cell development and inflammation.However,their role in antiviral innate immunity has not been elucidated...Protein arginine methyltransferases(PRMTs)play diverse biological roles and are specifically involved in immune cell development and inflammation.However,their role in antiviral innate immunity has not been elucidated.Viral infection triggers the TBK1–IRF3 signaling pathway to stimulate the production of type-I interferon,which mediates antiviral immunity.We performed a functional screen of the nine mammalian PRMTs for regulators of IFN-βexpression and found that PRMT6 inhibits the antiviral innate immune response.Viral infection also upregulated PRMT6 protein levels.We generated PRMT6-deficient mice and found that they exhibited enhanced antiviral innate immunity.PRMT6 deficiency promoted the TBK1–IRF3 interaction and subsequently enhanced IRF3 activation and type-I interferon production.Mechanistically,viral infection enhanced the binding of PRMT6 to IRF3 and inhibited the interaction between IRF3 and TBK1;this mechanism was independent of PRMT6 methyltransferase activity.Thus,PRMT6 inhibits antiviral innate immunity by sequestering IRF3,thereby blocking TBK1-IRF3 signaling.Our work demonstrates a methyltransferase-independent role for PRMTs.It also identifies a negative regulator of the antiviral immune response,which may protect the host from the damaging effects of an overactive immune system and/or be exploited by viruses to escape immune detection.展开更多
With the support by the National Natural Science Foundation of China,the research team directed by Prof.Cao Xuetao(曹雪涛)at the National Key Laboratory of Medical Molecular Biology&Department of Immunology,Chines...With the support by the National Natural Science Foundation of China,the research team directed by Prof.Cao Xuetao(曹雪涛)at the National Key Laboratory of Medical Molecular Biology&Department of Immunology,Chinese Academy of Medical Sciences,and the National Key Laboratory of Medical Immunology,Second Military Medical University,recently reported that RNA helicase DDX46is展开更多
An antiviral innate immune response involves induction of type I interferons(IFNs)and their subsequent autocrine and paracrine actions,but the underlying regulatory mechanisms are incompletely understood.Here we repor...An antiviral innate immune response involves induction of type I interferons(IFNs)and their subsequent autocrine and paracrine actions,but the underlying regulatory mechanisms are incompletely understood.Here we report that CYLD,a deubiquitinase that specifically digests lysine 63-linked ubiquitin chains,is required for antiviral host defense.Loss of CYLD renders mice considerably more susceptible to infection by vesicular stomatitis virus(VSV).Consistently,CYLD-deficient dendritic cells are more sensitive to VSV infection.This functional defect was not due to lack of type I IFN production but rather because of attenuated IFN receptor signaling.In the absence of CYLD,IFN-b is ineffective in the induction of antiviral genes and protection of cells from viral infection.These findings establish CYLD as a novel regulator of antiviral innate immunity and suggest a role for CYLD in regulating IFN receptor signaling.展开更多
The anatomical architecture of the human liver and the diversity of its immune components endow the liver with its physiological function of immune competence. Adaptive immunity is a major arm of the immune system tha...The anatomical architecture of the human liver and the diversity of its immune components endow the liver with its physiological function of immune competence. Adaptive immunity is a major arm of the immune system that is organized in a highly specialized and systematic manner, thus providing long-lasting protection with immunological memory. Adaptive immunity consists of humoral immunity and cellular immunity. Cellular immunity is known to have a crucial role in controlling infection, cancer and autoimmune disorders in the liver. In this article, we will focus on hepatic virus infections, hepatocellular carcinoma and autoimmune disorders as examples to illustrate the current understanding of the contribution of T cells to cellular immunity in these maladies. Cellular immune suppression is primarily responsible for chronic viral infections and cancer. However, an uncontrolled auto-reactive immune response accounts for autoimmunity. Consequently, these immune abnormalities are ascribed to the quantitative and functional changes in adaptive immune cells and their subsets, innate immunocytes, chemokines, cytokines and various surface receptors on immune cells. A greater understanding of the complex orchestration of the hepatic adaptive immune regulators during homeostasis and immune competence are much needed to identify relevant targets for clinical intervention to treat immunological disorders in the liver.展开更多
A complex network of cellular receptors,RNA targeting pathways,and small-molecule signaling provides robust plant immunity and tolerance to viruses.To maximize their fitness,viruses must evolve control mechanisms to b...A complex network of cellular receptors,RNA targeting pathways,and small-molecule signaling provides robust plant immunity and tolerance to viruses.To maximize their fitness,viruses must evolve control mechanisms to balance host immune evasion and plant-damaging effects.The genus Potyvirus comprises plant viruses characterized by RNA genomes that encode large polyproteins led by the P1 protease.A P1 autoinhibitory domain controls polyprotein processing,the release of a downstream functional RNAsilencing suppressor,and viral replication.Here,we show that P1Pro,a plum pox virus clone that lacks the P1 autoinhibitory domain,triggers complex reprogramming of the host transcriptome and high levels of abscisic acid(ABA)accumulation.A meta-analysis highlighted ABA connections with host pathways known to control RNA stability,turnover,maturation,and translation.Transcriptomic changes triggered by P1Pro infection or ABA showed similarities in host RNA abundance and diversity.Genetic and hormone treatment assays showed that ABA promotes plant resistance to potyviral infection.Finally,quantitative mathematical modeling of viral replication in the presence of defense pathways supported self-control of polyprotein processing kinetics as a viral mechanism that attenuates the magnitude of the host antiviral response.Overall,our findings indicate that ABA is an active player in plant antiviral immunity,which is nonetheless evaded by a self-controlled RNA virus.展开更多
Antiretroviral therapy against human immunodeficiency virus (HIV) is effective in controlling viral replication but cannot completely eliminate HIV due to the persistence of the HIV reservoir. Innate and adaptive immu...Antiretroviral therapy against human immunodeficiency virus (HIV) is effective in controlling viral replication but cannot completely eliminate HIV due to the persistence of the HIV reservoir. Innate and adaptive immune responses have been proposed to contribute to preventing HIV acquisition, controlling HIV replication and eliminating HIV-infected cells. However, the immune responses naturally induced in HIV-infected individuals rarely eradicate HIV infection, which may be caused by immune escape, an inadequate magnitude and breadth of immune responses, and immune exhaustion. Optimizing these immune responses may solve the problems of epitope escape and insufficient sustained memory responses. Moreover, immune interventions aimed at improving host immune response can reduce HIV reservoirs, which have become one focus in the development of innovative strategies to eliminate HIV reservoirs. In this review, we focus on the immune response against HIV and how antiviral immune responses affect HIV reservoirs. We also discuss the development of innovative strategies aiming to eliminate HIV reservoirs and promoting functional cure of HIV infection.展开更多
Chronic hepatitis B virus (HBV) infection progresses through distinct disease phases that are strongly associated with patient age. The so-called immune tolerant (IT) phase represents the classical early phase of ...Chronic hepatitis B virus (HBV) infection progresses through distinct disease phases that are strongly associated with patient age. The so-called immune tolerant (IT) phase represents the classical early phase of infection; it is associated with high levels of HBV replication and lack of clinical signs of liver Inflammation. Whether this phase of HBV infection is also associated with immunological features of "tolerance' has recently been challenged. Here, we review the data that dispute this concept of immune tolerance and then propose an alternative interpretation of the immunopathological events that take place during this early phase of CHB infection.展开更多
Tripartite motif(TRIM)family proteins are important effectors of innate immunity against viral infections.Here we identified TRIM35 as a regulator of TRAF3 activation.Deficiency in or inhibition of TRIM35 suppressed t...Tripartite motif(TRIM)family proteins are important effectors of innate immunity against viral infections.Here we identified TRIM35 as a regulator of TRAF3 activation.Deficiency in or inhibition of TRIM35 suppressed the production of type I interferon(IFN)in response to viral infection.777m35-deficient mice were more susceptible to influenza A virus(IAV)infection than were wild-type mice.TRIM35 promoted the RIG-Imediated signaling by catalyzing Lys63-linked polyubiquitination of TRAF3 and the subsequent formation of a signaling complex with VISA and TBK1.IAV PB2 polymerase countered the innate antiviral immune response by impeding the Lys63-linked polyubiquitination and activation of TRAF3.TRIM35 mediated Lys48-linked polyubiquitination and proteasomal degradation of IAV PB2,thereby antagonizing its suppression of TRAF3 activation.Our in vitro and in vivo findings thus reveal novel roles of TRIM35,through catalyzing Lys63-or Lys48-linked polyubiquitination,in RIG-I antiviral immunity and mechanism of defense against IAV infection.展开更多
SARS-CoV-2 is the pathogenic agent of COVID-19,which has evolved into a global pandemic.Compared with some other respiratory RNA viruses,SARS-CoV-2 is a poor inducer of type Ⅰ interferon(IFN).Here,we report that SARS...SARS-CoV-2 is the pathogenic agent of COVID-19,which has evolved into a global pandemic.Compared with some other respiratory RNA viruses,SARS-CoV-2 is a poor inducer of type Ⅰ interferon(IFN).Here,we report that SARS-CoV-2 nsp12,the viral RNA-dependent RNA polymerase(RdRp),suppresses host antiviral responses.SARS-CoV-2 nsp12 attenuated Sendai virus(SeV)-or poly(I:C)-induced IFN-β promoter activation in a dose-dependent manner.It also inhibited IFN promoter activation triggered by RIG-I,MDA5,MAVS,and IRF3 overexpression.Nsp12 did not impair IRF3 phosphorylation but suppressed the nuclear translocation of IRF3.Mutational analyses suggested that this suppression was not dependent on the polymerase activity of nsp12.Given these findings,our study reveals that SARS-CoV-2 RdRp can antagonize host antiviral innate immunity and thus provides insights into viral pathogenesis.展开更多
ISG20 is an interferon-inducible exonuclease that inhibits virus replication.Although ISG20 is thought to degrade viral RNA,the antiviral mechanism and specificity of ISG20 remain unclear.In this study,the antiviral r...ISG20 is an interferon-inducible exonuclease that inhibits virus replication.Although ISG20 is thought to degrade viral RNA,the antiviral mechanism and specificity of ISG20 remain unclear.In this study,the antiviral role of ovine ISG20(o ISG20)in bluetongue virus(BTV)infection was investigated.It was found that BTV infection upregulated the transcription of ovine ISG20(o ISG20)in a time-and BTV multiplicity of infection(MOI)-dependent manner.Overexpression of o ISG20 suppressed the production of BTV genome,proteins,and virus titer,whereas the knockdown of o ISG20 increased viral replication.o ISG20 was found to co-localize with BTV proteins VP4,VP5,VP6,and NS2,but only directly interacted with VP4.Exonuclease defective o ISG20 significantly decreased the inhibitory effect on BTV replication.In addition,the interaction of mutant o ISG20 and VP4 was weakened,suggesting that binding to VP4 was associated with the inhibition of BTV replication.The present data characterized the anti-BTV effect of o ISG20,and provides a novel clue for further exploring the inhibition mechanism of double-stranded RNA virus by ISG20.展开更多
基金Supported by the European Union-Next Generation EU,through the National Recovery and Resilience Plan of the Republic of Bulgaria,No.BG-RRP-2.004-0008.
文摘An overly exuberant immune response,characterized by a cytokine storm and uncontrolled inflammation,has been identified as a significant driver of severe coronavirus disease 2019(COVID-19)cases.Consequently,deciphering the intricacies of immune dysregulation in COVID-19 is imperative to identify specific targets for intervention and modulation.With these delicate dynamics in mind,immunomodulatory therapies have emerged as a promising avenue for miti-gating the challenges posed by COVID-19.Precision in manipulating immune pathways presents an opportunity to alter the host response,optimizing antiviral defenses while curbing deleterious inflammation.This review article compre-hensively analyzes immunomodulatory interventions in managing COVID-19.We explore diverse approaches to mitigating the hyperactive immune response and its impact,from corticosteroids and non-steroidal drugs to targeted biologics,including anti-viral drugs,cytokine inhibitors,JAK inhibitors,convalescent plasma,monoclonal antibodies(mAbs)to severe acute respiratory syndrome coronavirus 2,cell-based therapies(i.e.,CAR T,etc.).By summarizing the current evidence,we aim to provide a clear roadmap for clinicians and researchers navigating the complex landscape of immunomodulation in COVID-19 treatment.CS Glucocorticoids are among the most widely prescribed drugs with their immune-suppressive and anti-inflammatory effect[84].The current guidelines for the treatment of COVID-19 recommend against the use of dexamethasone or other systemic CS in non-hospitalized patients in the absence of another indication[70].The RECOVERY trial demonstrates the reduced 28-d mortality among hospitalized patients with COVID-19 using dexamethasone compared to the usual standard of care,along with other investigators,such as Ahmed and Hassan[85].The benefit of dexamethasone was seen only among participants receiving either oxygen alone or invasive mechanical ventilation at randomization but not among those receiving no respiratory support at enrollment[85].In a systematic review and meta-analysis,Albuquerque et al[86]showed that in comparison to tocilizumab,baricitinib,and sarilumab are associated with high probabilities of similar mortality reductions among hospitalized COVID-19 concurrently treated with CS.As a result of the absence of SARS-CoV-2-specific antiviral medications,the effectiveness of COVID-19 treatments is reduced.Several COVID-19 therapies are now under investigation.However,the majority of them lack specificity,efficacy,and safety[87].Immunotherapy is a ground-breaking medical treatment that manipulates the immune system to fight diseases.Translational research is rapidly progressing,recognized as a significant breakthrough in 2013[88].Among the immunotherapeutic options for treating COVID-19 are Immunoglobulin,CP,antibodies,mAbs(mAbs),NK cells,T cells,TLR,cytokine therapies and immune modulators.
文摘Subject Code:H19With the support by the National Natural Science Foundation of China,a collaborative study by the research groups led by Prof.Zhou Xi(周溪)from the State Key Laboratory of Virology,Wuhan Institute of Virology,Chinese Academy of Sciences and Prof.Qin Chengfeng(秦成峰)from Beijing Institute
基金This work was supported by the National Natural Science Foundation of China(32202278)the Chongqing Special Postdoctoral Science Foundation of Chinathe earmarked fund for China Agricultural Research System(CARS-26)。
文摘The Janus kinase/signal transducers and activators of transcription(JAK/STAT)signaling pathway play a pivotal role in innate immunity.Among invertebrates,Domeless receptors serve as the key upstream regulators of this pathway.In our study on Bactrocera dorsalis,we identified three cytokine receptors:BdDomeless1,BdDomeless2,and BdDomeless3.Each receptor encompasses five fibronectin-type-III-like(FN III)extracellular domains and a transmembrane domain.Furthermore,these receptors exhibit the increased responsiveness to diverse pathogenic challenges.Notably,only BdDomeless3 is upregulated during symbiont-like viral infections.Moreover,silencing BdDomeless3 enhanced the infectivity of Bactrocera dorsalis cripavirus(BdCV)and B.dorsalis picorna-like virus(BdPLV),underscoring BdDomeless3’s crucial role in antiviral defense of B.dorsalis.Following the suppression of Domeless3 expression,six antimicrobial peptide genes displayed decreased expression,potentially correlating with the rise in viral infectivity.To our knowledge,this is the first study identifying cytokine receptors associated with the JAK/STAT pathway in tephritid flies,shedding light on the immune mechanisms of B.dorsalis.
文摘The COVID-19 pandemic has revealed sex-based differences in anti-viral responses,with a higher rate of SARS-CoV-2 infections as well as a higher rate of morbidity and mortality in men than in women.Males and females also show disparate immune responses to COVID-19 infection,which may be important contributors to lower rates of infection,disease severity and deaths in women than in men.Here,the authors review sex differences in SARS-CoV-2 infections,anti-viral immunity and vaccine responses,putting forth the importance of sex,the underappreciated variables in vaccine response and disease infectivity.
基金This research was supported by grants from the National Natural Science Foundation of China (Grant Nos. 81273231,81172799 to Z. C. and 81102478, 81471947 to Y. X.).
文摘Autophagy plays important roles in modulating viral replication and antiviral immune response. Coronavirus infection is associated with the autophagic process, however, little is known about the mechanisms of autophagy induction and its contribution to coronavirus regulation of host innate responses. Here, we show that the membrane-associated papain-like protease PLP2 (PLP2-TM) of coronaviruses acts as a novel autophagy- inducing protein. Intriguingly, PLP2-TM induces incom- plete autophagy process by increasing the accumula- tion of autophagosomes but blocking the fusion of autophagosomes with lysosomes. Furthermore, PLP2- TM interacts with the key autophagy regulators, LC3 and Beclinl, and promotes Beclinl interaction with STING, the key regulator for antiviral IFN signaling. Finally, knockdown of Beclinl partially reverses PLP2-TM's inhibitory effect on innate immunity which resulting in decreased coronavirus replication. These results sug- gested that coronavirus papain-like protease induces incomplete autophagy by interacting with Beclinl, which in turn modulates coronavirus replication and antiviral innate immunity.
基金supported by grants from the National Natural Science Foundation of China (31572324)the General Program of Natural Science Foundation of the Higher Education Institutions of Jiangsu Province, China (16KJB180017)+2 种基金the College Students’ Innovation and Entrepreneurship Training Program Project of Jiangsu Province, China (201813843009Y)the Jiangsu Agricultural Scientific Self-innovation Fund, China (CX[15]1053)a grant from Priority Academic Program Development of Jiangsu Higher Education Institutions, China
文摘Toll-like receptors(TLRs) are the critical superfamily homologues that initiate sensing of the invasion of pathogens by the Toll pathway. As one of several intracellular nucleic acid-sensing TLRs, TLR13 is activated by an unmethylated motif present in the large ribosomal subunit of bacterial RNA. However, little attention has been paid to the function of TLR13 gene homologue from Laodelphax striatellus(designated as LsToll-13) in the immune response to rice stripe virus(RSV). Herein, LsToll-13 was cloned and characterized using RACE-PCR. Phylogenetic analysis showed that LsToll-13 was clustered with the TLR13 from six insects. Real-time PCR analysis demonstrated that the expression level of LsToll-13 was significantly reduced in L. striatellus with RSV infection compared with that in the naive strain. When the expression of LsToll-13 was significantly up-regulated at 6 h after bacterial infection, the expression of ribonucleoprotein(RNP) indicated that the RSV titer in the host insect was significantly suppressed. Upon knockdown of LsToll-13, using RNA interference(RNAi) in L. striatellus, the expression level of RNP was significantly increased with enhanced RSV accumulation, suggesting that LsToll-13 potentially protects L. striatellus from RSV infection. Taken together, our results indicated that LsToll-13 might be involved in the immune response of L. striatellus to RSV infection, and provided a new insight into further elucidating the molecular mechanisms of complex pathogen-host interactions and integrative pest management.
基金This work was supported by grants from the National Natural Science Foundation of China(31730026,81930039,and 81525012).
文摘Stimulator of interferon genes(STING)is an adaptor protein that is critical for effective innate antiviral and antitumor immunity.The activity of STING is heavily regulated by protein ubiquitination,which is fine-tuned by both E3 ubiquitin ligases and deubiquitinases.Here,we report that the deubiquitinase OTUD5 interacts with STING,cleaves its K48-linked polyubiquitin chains,and promotes its stability.Consistently,knockout of OTUD5 resulted in faster turnover of STING and subsequently impaired type I IFN signaling following cytosolic DNA stimulation.More importantly,Lyz2-Cre Otud5^(fl/Y) mice and CD11-Cre Otud5^(fl/Y) mice showed more susceptibility to herpes simplex virus type 1(HSV-1)infection and faster development of melanomas than their corresponding control littermates,indicating that OTUD5 is indispensable for STING-mediated antiviral and antitumor immunity.Our data suggest that OTUD5 is a novel checkpoint in the cGAS-STING cytosolic DNA sensing pathway.
基金supported by the National Basic Research Program of China(2020YFA0804000,2020YFC0842000,2020YFA0112200,2021YFC2301703)Strategic Priority Research Program of the Chinese Academy of Sciences(XDB32010100)+6 种基金Special Associate Research Program of the Chinese Academy of Sciences(E1290601)National Natural Science Foundation of China(32122037,81891001,32192411,32100512,U1902215)Collaborative Research Fund of the Chinese Institute for Brain Research,Beijing(2020-NKX-PT-03)CAS Project for Young Scientists in Basic Research(YSBR-013)Young Elite Scientist Sponsorship Program by the China Association for Science and Technology(2020QNRC001)National Resource Center for Non-Human Primates。
文摘Infection with severe acute respiratory syndrome coronavirus 2(SARS-CoV-2) causes diverse clinical manifestations and tissue injuries in multiple organs.However, cellular and molecular understanding of SARS-CoV-2 infection-associated pathology and immune defense features in different organs remains incomplete. Here, we profiled approximately 77 000single-nucleus transcriptomes of the lung, liver,kidney, and cerebral cortex in rhesus macaques(Macaca mulatta) infected with SARS-CoV-2 and healthy controls. Integrated analysis of the multiorgan dataset suggested that the liver harbored the strongest global transcriptional alterations. We observed prominent impairment in lung epithelial cells, especially in AT2 and ciliated cells, and evident signs of fibrosis in fibroblasts. These lung injury characteristics are similar to those reported in patients with coronavirus disease 2019(COVID-19).Furthermore, we found suppressed MHC class I/II molecular activity in the lung, inflammatory response in the liver, and activation of the kynurenine pathway,which induced the development of an immunosuppressive microenvironment. Analysis of the kidney dataset highlighted tropism of tubule cells to SARS-CoV-2, and we found membranous nephropathy(an autoimmune disease) caused by podocyte dysregulation. In addition, we identified the pathological states of astrocytes and oligodendrocytes in the cerebral cortex, providing molecular insights into COVID-19-related neurological implications. Overall, our multi-organ single-nucleus transcriptomic survey of SARS-CoV-2-infected rhesus macaques broadens our understanding of disease features and antiviral immune defects caused by SARS-CoV-2 infection,which may facilitate the development of therapeutic interventions for COVID-19.
基金supported by grants from the National Key R&D program of China(2018YFA0507401)National Natural Science Foundation of China(31390431,31522019,81471568,80178104,and 31770945)the CAMS Innovation Fund for Medical Sciences(2016-12M-1-003).
文摘Protein arginine methyltransferases(PRMTs)play diverse biological roles and are specifically involved in immune cell development and inflammation.However,their role in antiviral innate immunity has not been elucidated.Viral infection triggers the TBK1–IRF3 signaling pathway to stimulate the production of type-I interferon,which mediates antiviral immunity.We performed a functional screen of the nine mammalian PRMTs for regulators of IFN-βexpression and found that PRMT6 inhibits the antiviral innate immune response.Viral infection also upregulated PRMT6 protein levels.We generated PRMT6-deficient mice and found that they exhibited enhanced antiviral innate immunity.PRMT6 deficiency promoted the TBK1–IRF3 interaction and subsequently enhanced IRF3 activation and type-I interferon production.Mechanistically,viral infection enhanced the binding of PRMT6 to IRF3 and inhibited the interaction between IRF3 and TBK1;this mechanism was independent of PRMT6 methyltransferase activity.Thus,PRMT6 inhibits antiviral innate immunity by sequestering IRF3,thereby blocking TBK1-IRF3 signaling.Our work demonstrates a methyltransferase-independent role for PRMTs.It also identifies a negative regulator of the antiviral immune response,which may protect the host from the damaging effects of an overactive immune system and/or be exploited by viruses to escape immune detection.
文摘With the support by the National Natural Science Foundation of China,the research team directed by Prof.Cao Xuetao(曹雪涛)at the National Key Laboratory of Medical Molecular Biology&Department of Immunology,Chinese Academy of Medical Sciences,and the National Key Laboratory of Medical Immunology,Second Military Medical University,recently reported that RNA helicase DDX46is
基金supported by the National Institutes of Health grant AI064639.
文摘An antiviral innate immune response involves induction of type I interferons(IFNs)and their subsequent autocrine and paracrine actions,but the underlying regulatory mechanisms are incompletely understood.Here we report that CYLD,a deubiquitinase that specifically digests lysine 63-linked ubiquitin chains,is required for antiviral host defense.Loss of CYLD renders mice considerably more susceptible to infection by vesicular stomatitis virus(VSV).Consistently,CYLD-deficient dendritic cells are more sensitive to VSV infection.This functional defect was not due to lack of type I IFN production but rather because of attenuated IFN receptor signaling.In the absence of CYLD,IFN-b is ineffective in the induction of antiviral genes and protection of cells from viral infection.These findings establish CYLD as a novel regulator of antiviral innate immunity and suggest a role for CYLD in regulating IFN receptor signaling.
文摘The anatomical architecture of the human liver and the diversity of its immune components endow the liver with its physiological function of immune competence. Adaptive immunity is a major arm of the immune system that is organized in a highly specialized and systematic manner, thus providing long-lasting protection with immunological memory. Adaptive immunity consists of humoral immunity and cellular immunity. Cellular immunity is known to have a crucial role in controlling infection, cancer and autoimmune disorders in the liver. In this article, we will focus on hepatic virus infections, hepatocellular carcinoma and autoimmune disorders as examples to illustrate the current understanding of the contribution of T cells to cellular immunity in these maladies. Cellular immune suppression is primarily responsible for chronic viral infections and cancer. However, an uncontrolled auto-reactive immune response accounts for autoimmunity. Consequently, these immune abnormalities are ascribed to the quantitative and functional changes in adaptive immune cells and their subsets, innate immunocytes, chemokines, cytokines and various surface receptors on immune cells. A greater understanding of the complex orchestration of the hepatic adaptive immune regulators during homeostasis and immune competence are much needed to identify relevant targets for clinical intervention to treat immunological disorders in the liver.
基金supported by funds to J.A.G.from the Ministerio de Ciencia e Innovaciòn(Spain),grants BIO2016-80572-R and PID2019-109380RBI00/AEI/10.13039/501100011033(AEI-FEDER)funded by grant K124705 from the National Research Development and Innovation Office(Hungary)+2 种基金S.M.-B.by grant 2017 SGR 980 from the Generalitat de Catalunya(Spain)supported by NIH grant HG006620the recipient of a post-doctoral fellowship from Academia Sinica(Taiwan).
文摘A complex network of cellular receptors,RNA targeting pathways,and small-molecule signaling provides robust plant immunity and tolerance to viruses.To maximize their fitness,viruses must evolve control mechanisms to balance host immune evasion and plant-damaging effects.The genus Potyvirus comprises plant viruses characterized by RNA genomes that encode large polyproteins led by the P1 protease.A P1 autoinhibitory domain controls polyprotein processing,the release of a downstream functional RNAsilencing suppressor,and viral replication.Here,we show that P1Pro,a plum pox virus clone that lacks the P1 autoinhibitory domain,triggers complex reprogramming of the host transcriptome and high levels of abscisic acid(ABA)accumulation.A meta-analysis highlighted ABA connections with host pathways known to control RNA stability,turnover,maturation,and translation.Transcriptomic changes triggered by P1Pro infection or ABA showed similarities in host RNA abundance and diversity.Genetic and hormone treatment assays showed that ABA promotes plant resistance to potyviral infection.Finally,quantitative mathematical modeling of viral replication in the presence of defense pathways supported self-control of polyprotein processing kinetics as a viral mechanism that attenuates the magnitude of the host antiviral response.Overall,our findings indicate that ABA is an active player in plant antiviral immunity,which is nonetheless evaded by a self-controlled RNA virus.
基金This work was supported by grants from the National Natural Science Foundation of China (Nos. NSFC, 81974303 to BS, and 82072271 to TZ)the High-Level Public Health Specialized Talents Project of Beijing Municipal Health Commission (Nos. 2022-1-007 to TZ and 2022-2-018 to BS)+4 种基金the "Climbing the peak (Dengfeng) " Talent Training Program of Beijing Hospitals Authority (No. DFL20191701 to TZ)the Beijing Health Technologies Promotion Program (No. BHTPP2020 to TZ)the Beijing Key Laboratory for HIV/AIDS Research (No. BZ0089)the ANRS (Agence Nationale de Recherches sur le SIDA et les hépatites virales)the Investissements d’Avenir program managed by the ANR under reference ANR-10-LABX-77 and EHVA (No. 681032, Horizon 2020) .
文摘Antiretroviral therapy against human immunodeficiency virus (HIV) is effective in controlling viral replication but cannot completely eliminate HIV due to the persistence of the HIV reservoir. Innate and adaptive immune responses have been proposed to contribute to preventing HIV acquisition, controlling HIV replication and eliminating HIV-infected cells. However, the immune responses naturally induced in HIV-infected individuals rarely eradicate HIV infection, which may be caused by immune escape, an inadequate magnitude and breadth of immune responses, and immune exhaustion. Optimizing these immune responses may solve the problems of epitope escape and insufficient sustained memory responses. Moreover, immune interventions aimed at improving host immune response can reduce HIV reservoirs, which have become one focus in the development of innovative strategies to eliminate HIV reservoirs. In this review, we focus on the immune response against HIV and how antiviral immune responses affect HIV reservoirs. We also discuss the development of innovative strategies aiming to eliminate HIV reservoirs and promoting functional cure of HIV infection.
文摘Chronic hepatitis B virus (HBV) infection progresses through distinct disease phases that are strongly associated with patient age. The so-called immune tolerant (IT) phase represents the classical early phase of infection; it is associated with high levels of HBV replication and lack of clinical signs of liver Inflammation. Whether this phase of HBV infection is also associated with immunological features of "tolerance' has recently been challenged. Here, we review the data that dispute this concept of immune tolerance and then propose an alternative interpretation of the immunopathological events that take place during this early phase of CHB infection.
基金The work was supported by the National Key Research and Development Program of China(2016YFD0500205)the National Natural Science Foundation of China(NSFC)(Grant Nos.31521005,31672582,31422054,and 31472215)+1 种基金the Natural Science Foundation of Heilongjiang Province(JQ2019C005)by the Central Public-Interest Scientific Institution Basal Research Fund(No.Y2017JC35).
文摘Tripartite motif(TRIM)family proteins are important effectors of innate immunity against viral infections.Here we identified TRIM35 as a regulator of TRAF3 activation.Deficiency in or inhibition of TRIM35 suppressed the production of type I interferon(IFN)in response to viral infection.777m35-deficient mice were more susceptible to influenza A virus(IAV)infection than were wild-type mice.TRIM35 promoted the RIG-Imediated signaling by catalyzing Lys63-linked polyubiquitination of TRAF3 and the subsequent formation of a signaling complex with VISA and TBK1.IAV PB2 polymerase countered the innate antiviral immune response by impeding the Lys63-linked polyubiquitination and activation of TRAF3.TRIM35 mediated Lys48-linked polyubiquitination and proteasomal degradation of IAV PB2,thereby antagonizing its suppression of TRAF3 activation.Our in vitro and in vivo findings thus reveal novel roles of TRIM35,through catalyzing Lys63-or Lys48-linked polyubiquitination,in RIG-I antiviral immunity and mechanism of defense against IAV infection.
基金supported by grants from the National Major Sciences&Technology Project for Control and Prevention of Major Infectious Diseases in China(2018ZX10733403 and 2018ZX10101001 to Z.X.,2018ZX10301401 to X.L. and Z.Z.)the National Natural Science Foundation of China(81930063,81971948,81772201,and 31670169 to J.W.,X.L.,Z.X.,and Z.Z.)+1 种基金the National Key R&D Program of China(2020YFA0707600)the Chinese Academy of Medical Sciences(CAMS)Innovation Fund for Medical Sciences(2016-I2M-1-014 to J.W.).
文摘SARS-CoV-2 is the pathogenic agent of COVID-19,which has evolved into a global pandemic.Compared with some other respiratory RNA viruses,SARS-CoV-2 is a poor inducer of type Ⅰ interferon(IFN).Here,we report that SARS-CoV-2 nsp12,the viral RNA-dependent RNA polymerase(RdRp),suppresses host antiviral responses.SARS-CoV-2 nsp12 attenuated Sendai virus(SeV)-or poly(I:C)-induced IFN-β promoter activation in a dose-dependent manner.It also inhibited IFN promoter activation triggered by RIG-I,MDA5,MAVS,and IRF3 overexpression.Nsp12 did not impair IRF3 phosphorylation but suppressed the nuclear translocation of IRF3.Mutational analyses suggested that this suppression was not dependent on the polymerase activity of nsp12.Given these findings,our study reveals that SARS-CoV-2 RdRp can antagonize host antiviral innate immunity and thus provides insights into viral pathogenesis.
基金the National Key Research and Development Program of China(2021YFD18005022017YFD0502304)+2 种基金National Natural Science Foundation of China(31672562)NBCITS(CARS-37)ASTIP(CAAS-ASTIP-2016-LVRI)。
文摘ISG20 is an interferon-inducible exonuclease that inhibits virus replication.Although ISG20 is thought to degrade viral RNA,the antiviral mechanism and specificity of ISG20 remain unclear.In this study,the antiviral role of ovine ISG20(o ISG20)in bluetongue virus(BTV)infection was investigated.It was found that BTV infection upregulated the transcription of ovine ISG20(o ISG20)in a time-and BTV multiplicity of infection(MOI)-dependent manner.Overexpression of o ISG20 suppressed the production of BTV genome,proteins,and virus titer,whereas the knockdown of o ISG20 increased viral replication.o ISG20 was found to co-localize with BTV proteins VP4,VP5,VP6,and NS2,but only directly interacted with VP4.Exonuclease defective o ISG20 significantly decreased the inhibitory effect on BTV replication.In addition,the interaction of mutant o ISG20 and VP4 was weakened,suggesting that binding to VP4 was associated with the inhibition of BTV replication.The present data characterized the anti-BTV effect of o ISG20,and provides a novel clue for further exploring the inhibition mechanism of double-stranded RNA virus by ISG20.