p204 is a member of the interferon-inducible p200 family proteins in mice.The p200 family has been reported to be multifunctional regulators of cell proliferation,differentiation,apoptosis and senescence.Interferon-in...p204 is a member of the interferon-inducible p200 family proteins in mice.The p200 family has been reported to be multifunctional regulators of cell proliferation,differentiation,apoptosis and senescence.Interferon-inducible protein 16(IFI16)is regarded as the human ortholog of p204 in several studies.This is possibly due to the similarity of their structures.However the consistency of their functions is still elusive.Currently,an emerging focus has been placed upon the role of the p200 proteins as sensors for microbial DNA in innate immune responses and provides new insights into infections as well as autoimmune diseases.This review specially focuses on IFI16 and p204,the member of p200 family in human and murine respectively,and their pathophysiological roles in innate immune responses,cell differentiation and proliferation.展开更多
An ancient conflict between hosts and pathogens has driven the innate and adaptive arms of immunity.Knowledge about this interplay can not only help us identify biological mechanisms but also reveal pathogen vulnerabi...An ancient conflict between hosts and pathogens has driven the innate and adaptive arms of immunity.Knowledge about this interplay can not only help us identify biological mechanisms but also reveal pathogen vulnerabilities that can be leveraged therapeutically.The humoral response to SARS-CoV-2 infection has been the focus of intense research,and the role of the innate immune system has received significantly less attention.Here,we review current knowledge of the innate immune response to SARS-CoV-2 infection and the various means SARS-CoV-2 employs to evade innate defense systems.We also consider the role of innate immunity in SARS-CoV-2 vaccines and in the phenomenon of long COVID.展开更多
The intracellular pathogen Mycobacterium tuberculosis(Mtb)can survive in the host and cause disease by interfering with a variety of cellular functions.The mammalian cell entry 2(mce2)operon of Mtb has been shown to c...The intracellular pathogen Mycobacterium tuberculosis(Mtb)can survive in the host and cause disease by interfering with a variety of cellular functions.The mammalian cell entry 2(mce2)operon of Mtb has been shown to contribute to tuberculosis pathogenicity.However,little is known about the regulatory roles of Mtb Mce2 family proteins towards host cellular functions.Here we show that the Mce2 family protein Mce2E suppressed the macrophage innate immune response and promoted epithelial cell proliferation.Mce2E inhibited activation of the extracellular signal-regulated kinase(ERK)and Jun N-terminal kinase(JNK)mitogen-activated protein kinase(MAPK)signaling pathways in a non-canonical D motif(a MAPK-docking motif)-dependent manner,leading to reduced expression of TNF and IL-6 in macrophages.Furthermore,Mce2E promoted proliferation of human lung epithelium-derived lung adenoma A549 cells by inhibiting K48-linked polyubiquitination of eEF1A1 in aβstrand region-dependent manner.In summary,Mce2E is a novel multifunctional Mtb virulence factor that regulates host cellular functions in a niche-dependent manner.Our data suggest a potential novel target for TB therapy.展开更多
MITA is a central adaptor in innate immune responses to DNA viruses.The mechanisms responsible for recruitment of downstream kinase TBK1 and the transcription factor IRF3 to MITA remains enigmatic.Here we identified Z...MITA is a central adaptor in innate immune responses to DNA viruses.The mechanisms responsible for recruitment of downstream kinase TBK1 and the transcription factor IRF3 to MITA remains enigmatic.Here we identified ZDHHC11,a member of DHHC palmitoyl transferase family,as a positive regulator of DNA virus-triggered signaling.Overexpression of ZDHHC11 activated the IFN-βpromoter,while ZDHHC11-deficiency specifically impaired DNA virus HSV-1-induced transcription of downstream antiviral genes.Zdhhc11^(−/−)mice exhibited lower serum cytokine levels and higher lethality after HSV-1 infection.Mechanistically,ZDHHC11 facilitated the optimal recruitment of IRF3 to MITA.Our findings support an important role for ZDHHC11 in mediating MITA-dependent innate immune responses against DNA viruses.展开更多
The disease coronavirus disease 2019(COVID-19)is a severe respiratory illness that has emerged as a devastating health problem worldwide.The disease outcome is heterogeneous,and severity is likely dependent on the imm...The disease coronavirus disease 2019(COVID-19)is a severe respiratory illness that has emerged as a devastating health problem worldwide.The disease outcome is heterogeneous,and severity is likely dependent on the immunity of infected individuals and comorbidities.Although symptoms of the disease are primarily associated with respiratory problems,additional infection or failure of other vital organs are being reported.Emerging reports suggest a quite common co-existence of gastrointestinal(GI)tract symptoms in addition to respiratory symptoms in many COVID-19 patients,and some patients show just the GI symptoms.The possible cause of the GI symptoms could be due to direct infection of the epithelial cells of the gut,which is supported by the fact that(1)The intestinal epithelium expresses a high level of angiotensin-converting enzyme-2 and transmembrane protease serine 2 protein that are required for the severe acute respiratory syndrome coronavirus 2(SARS-CoV-2)entry into the cells;(2)About half of the severe COVID-19 patients show viral RNA in their feces and various parts of the GI tract;and(3)SARS-CoV-2 can directly infect gut epithelial cells in vitro(gut epithelial cells and organoids)and in vivo(rhesus monkey).The GI tract seems to be a site of active innate and adaptive immune responses to SARS-CoV-2 as clinically,stool samples of COVID-19 patients possess proinflammatory cytokines(interleukin 8),calprotectin(neutrophils activity),and immunoglobulin A antibodies.In addition to direct immune activation by the virus,impairment of GI epithelium integrity can evoke immune response under the influence of systemic cytokines,hypoxia,and changes in gut microbiota(dysbiosis)due to infection of the respiratory system,which is confirmed by the observation that not all of the GI symptomatic patients are viral RNA positive.This review comprehensively summarizes the possible GI immunomodulation by SARS-CoV-2 that could lead to GI symptoms,their association with disease severity,and potential therapeutic interventions.展开更多
The eicosanoid signaling pathway mediates insect immune reactions to a wide range of stimuli. This pathway begins with the biosynthesis of arachidonic acid (AA) from the hydrolysis of phospholipids catalyzed by phosph...The eicosanoid signaling pathway mediates insect immune reactions to a wide range of stimuli. This pathway begins with the biosynthesis of arachidonic acid (AA) from the hydrolysis of phospholipids catalyzed by phospholipase A_(2) (PLA_(2)). We report here that the PLA_(2) inhibitor, dexamethasone (DEX), impaired the innate immune response including nodulation, encapsulation, and melanization in Ostrinia furnacalis larvae, while AA partially reversed these effects of DEX. We cloned a full-length complementary DNA encoding a PLA_(2), designated as OfsPLA_(2), from O. furnacalis. The open reading frame of OfsPLA_(2) encodes a 195-amino acid residue protein with a 22-residue signal peptide. Sequence alignment analyses indicated that O. furnacalis PLA_(2) might be a Group III secretory PLA_(2). The highest transcript levels of OfsPLA_(2) were detected in the fat body, and its transcript levels increased dramatically after infection with Escherichia coli, Micrococcus luteus, or Beauveria bassiana. Recombinant OfsPLA_(2) significantly induced prophenoloxidase (PPO) activation in larval hemolymph in the presence of Ca^(2+) and encapsulation of agarose beads. Injection of recombinant OfsPLA_(2) into larvae resulted in increased transcript levels of attacin, defencin, and moricin-3 genes. Our results demonstrate the involvement of the eicosanoid signaling pathway in the innate immune response of O. furnacalis larvae and provide new information about the roles of O. furnacalis secretory PLA_(2) in activating PPO and antimicrobial peptide production.展开更多
Evolving data show a variable expression of clinical neurological manifestations in patients suffering with coronavirus disease 2019(COVID-19)from early disease onset.The most frequent symptoms and signs are fatigue,d...Evolving data show a variable expression of clinical neurological manifestations in patients suffering with coronavirus disease 2019(COVID-19)from early disease onset.The most frequent symptoms and signs are fatigue,dizziness,impaired consciousness,ageusia,anosmia,radicular pain,and headache,as well as others.Based on the high number of series of cases reported,there is evidence for the implication of the immune system in the pathological mechanism of COVID-19.Although the exact role of the immunological mechanism is not elucidated,two main mechanisms are suggested which implicate the direct effect of severe acute respiratory syndrome coronavirus 2 infection in the central nervous system and neuroinflammation.In the context of neurological manifestations associated with COVID-19,neuropsychiatric disorders show an exacerbation and are described by symptoms and signs such as depression,anxiety,mood alterations,psychosis,post-traumatic stress disorder,delirium,and cognitive impairment,which appear to be common in COVID-19 survivors.A worsened score on psychopathological measures is seen in those with a history of psychiatric comorbidities.We review the neuropsychiatric manifestations associated with COVID-19 and some critical aspects of the innate and adaptive immune system involved in mental health disorders occurring in COVID-19.展开更多
Activation of the TAK1 signalosome is crucial for mediating the innate immune response to pathogen invasion and is regulated by multiple layers of posttranslational modifications,including ubiquitination,SUMOylation,a...Activation of the TAK1 signalosome is crucial for mediating the innate immune response to pathogen invasion and is regulated by multiple layers of posttranslational modifications,including ubiquitination,SUMOylation,and phosphorylation;however,the underlying molecular mechanism is not fully understood.In this study,TRIM60 negatively regulated the formation and activation of the TAK1 signalosome.Deficiency of TRIM60 in macrophages led to enhanced MAPK and NF-κB activation,accompanied by elevated levels of proinflammatory cytokines but not IFN-I.Immunoprecipitation-mass spectrometry assays identified TAB2 as the target of TRIM60 for SUMOylation rather than ubiquitination,resulting in impaired formation of the TRAF6/TAB2/TAK1 complex and downstream MAPK and NF-κB pathways.The SUMOylation sites of TAB2 mediated by TRIM60 were identified as K329 and K562;substitution of these lysines with arginines abolished the SUMOylation of TAB2.In vivo experiments showed that TRIM60-deficient mice showed an elevated immune response to LPS-induced septic shock and L.monocytogenes infection.Our data reveal that SUMOylation of TAB2 mediated by TRIM60 is a novel mechanism for regulating the innate immune response,potentially paving the way for a new strategy to control antibacterial immune responses.展开更多
Objective: This study was designed to evaluate whether p62/SQSTM1 (hereafter referred to as p62) is involved in the immune response of macrophages against challenge byCandida albicans (C. albicans).Methods: We culture...Objective: This study was designed to evaluate whether p62/SQSTM1 (hereafter referred to as p62) is involved in the immune response of macrophages against challenge byCandida albicans (C. albicans).Methods: We cultured bone marrow-derived macrophages (BMDMs) to investigate the immune response to challenge byC. albicans. The p62 gene was knocked down by transfection with p62 small interfering RNA (siRNA) in the p62 siRNA group. BMDMs transfected with nonsense siRNA served as the negative control (NC) group. These two groups of BMDMs were challenged withC. albicans in vitro. We detected p62 expression through quantitative reverse transcription PCR and western blotting. The phagocytosis ability of BMDMs was evaluated by flow cytometry and microscopic examination using an Olympus FV1000 laser scanning confocal microscope. Moreover, we determined the level of reactive oxygen species (ROS) in BMDMs. The mRNA levels of proinflammatory cytokines were determined by quantitative reverse transcription PCR.Results: After stimulation byC. albicans, the relative expression of p62 mRNA was increased in a dose-dependent manner, the relative expression of p62 and the ratio of BMDMs toC. albicans is 1.893 ± 0.2156 (1:1,P < 0.05), 2.873 ± 0.4787 (1:3,P < 0.05) and 3.556 ± 0.2892 (1:5,P < 0.01). The p62 protein level was also increased. After transfection with p62 siRNA, the mRNA and protein levels of p62 were significantly decreased in BMDMs (P < 0.05). After 0.5, 1 and 2 hours of co-culture of BMDMs withC. albicans, flow cytometry showed that the phagocytosis rates ofC. albicans by BMDMs were significantly lower in the p62 siRNA group than in the NC group (39.70 ± 1.69%vs. 55.23 ± 0.72%, 46.70 ± 0.89%vs. 60.80 ± 1.78%, 51.90 ± 0.98%vs. 64.43 ± 2.0%, respectively, allP < 0.05). Consistent results were seen in the production of ROS (4269 ± 392.6vs. 13426 ± 1859.7, 4967 ± 721.2vs. 13687 ± 2611.2, 7647 ± 1950.0vs. 17719 ± 1814.2, respectively, allP < 0.05). The ROS levels were higher in BMDMs of the NC group than in BMDMs transfected with p62 siRNA at 0.5, 1, and 2 hours after treatment withC. albicans. BMDMs was co-cultured withC. albicans for 4 and 12 hours, the mRNA levels of interleukin-1β and interleukin-18 in NCs were also higher than p62 siRNA group, interleukin-1β: (6.14 ± 1.63vs. 12.12 ± 0.54, 8.81 ± 0.86vs. 26.2 ± 4.67, respectively, allP < 0.05), IL-18: (0.38 ± 0.02vs. 0.97 ± 0.06, 0.44 ± 0.02vs. 2.23 ± 0.46, respectively, allP < 0.05).Conclusion: p62 plays an important role in the process of phagocytosis in BMDMs challenged byC. albicans through ROS production and expression of proinflammatory cytokines.展开更多
The coronavirus disease 2019(COVID-19)pandemic caused by severe acute respiratory syndrome coronavirus 2(SARS-CoV-2)represents a major public health threat worldwide.Insight into protective and pathogenic aspects of S...The coronavirus disease 2019(COVID-19)pandemic caused by severe acute respiratory syndrome coronavirus 2(SARS-CoV-2)represents a major public health threat worldwide.Insight into protective and pathogenic aspects of SARS-CoV-2 immune responses is critical to work out effective therapeutics and develop vaccines for controlling the disease.Here,we review the present literature describing the innate and adaptive immune responses including innate immune cells,cytokine responses,antibody responses and T cell responses against SARS-CoV-2 in human infection,as well as in AEC2-humanized mouse infection.We also summarize the now known and unknown about the role of the SARS-CoV-2 immune responses.By better understanding the mechanisms that drive the immune responses,we can tailor treatment strategies at specific disease stages and improve our response to this worldwide public health threat.展开更多
Objective::In order to study the important role and molecular mechanism of Brevinin-2 family antimicrobial peptide Brevinin-2ISb in methicillin-resistant Staphylococcus aureus(MRSA)infection of Caenorhabditis(C.)elega...Objective::In order to study the important role and molecular mechanism of Brevinin-2 family antimicrobial peptide Brevinin-2ISb in methicillin-resistant Staphylococcus aureus(MRSA)infection of Caenorhabditis(C.)elegans,and to find the optimal therapeutic concentration of Brevinin-2ISb.Methods::By using a C.elegans model and MRSA infection modelto study the therapeutic effect of different concentrations of Brevinin-2ISb on C.elegans.Real-time PCR was used for investigating the effect of Brevinin-2ISb on the downstream gene expression of DAF-2/DAF-16 innate immune pathway and the major virulence factor gene expression of MRSA.With protein activity tests to study the inhibitory effect of Brevinin-2ISb on MRSA virulence factor protein activity.Finally,laser confocal imaging was carried out to observe real-time expression and distribution of downstream antimicrobial proteins to further prove the effect of Brevinin-2ISb on the activation of DAF-2/DAF-16 pathway by in vivo imaging.All animal study procedures were approved by the Academic Committee at Xidian University and Xi’an Jiaotong University Animal Care and Use Committee,China(approval No.JGC201207)on July 15,2017.Results::Host immunity was largely enhanced by Brevinin-2ISb,and the expression of staphylococcal enterotoxin genes,as well as virulence factors,was suppressed by Brevinin-2ISb.Indeed,the expression of many C.elegans innate immune genes,including lys-7,spp-1,K05D8.5 and C29F3.7,was induced by Brevinin-2ISb.In particular,robust,sustained expression of the antibacterial gene lys-7 was observed after Brevinin-2ISb treatment,resulting in increased protein levels.These effects correlated with a reduction in the MRSA-mediated death of the C.elegans host.Low concentrations of Brevinin-2ISb exhibited very low hemolytic activity,and may play a positive role in host innate immunity.Specifically,activation of the DAF-2/DAF-16 pathway appears to be essential for immune activation in C.elegans treated with Brevinin-2ISb.Based on the evolutionary conservation of innate immune pathways,our results suggest that Brevinin-2ISb not only has strong antibacterial activity,but may also enhance the innate immune response in humans.This study demonstrates that Brevinin-2ISb-related peptides are potential candidates for the development of novel anti-inflammatory or anti-microbial drugs.Conclusion::Antimicrobial peptide Brevinin-2ISb effectively inhibits MRSA at low concentration.This antimicrobial peptide can prolong the life of MRSA-infected C.elegans,has very low hemolytic activity and inhibits the activity and expression of various MRSA virulence factors.More importantly,Brevinin-2ISb activated the expression of antimicrobial genes downstream of DAF-2/DAF-16,which enhanced the MRSA resistance of C.elegans.This peptide could be used as the basis for developing new drugs to replace antibiotics.展开更多
The cyclic GMP-AMP (cGAMP) synthase (cGAS) plays a critical role in host defense by sensing cytosollc DNA derived from microbial pathogens or mls-located cellular DNA.Upon DNA binding,cGAS utilizes GTP and ATP as subs...The cyclic GMP-AMP (cGAMP) synthase (cGAS) plays a critical role in host defense by sensing cytosollc DNA derived from microbial pathogens or mls-located cellular DNA.Upon DNA binding,cGAS utilizes GTP and ATP as substrates to synthesize cGAMP,leading to MITA-mediated innate immune response.In this study,we identified the phosphatase PPP6C as a negative regulator of cGASmediated innate immune response.PPP6C is constitutively associated with cGAS in un-stimulated cells.DNA virus infection causes rapid disassociation of PPP6C from cGAS,resulting in phosphorylation of human cGAS S435 or mouse cGAS S420 in its catalytic pocket.Mutation of this eerine residue of cGAS impairs its ability to synthesize cGAMP upon DNA virus infection.In vitro experiments indicate that S420-phosphorylated mcGAS has higher affinity to GTP and enzymatic activity.PPP6Cdeficiency promotes innate immune response to DNA virus in various cells.Our findings suggest that PPP6Cmediated dephosphorylation of a catalytic pocket serine residue of cGAS impairs its substrate binding activity and innate immune response,which provides a mechanism for keeping the DNA sensor cGAS inactive in the absence of infection to avoid autoimmune response.展开更多
TET2,a member of ten-eleven translocation(TET)family as a-ketoglutarate-and Fe2+-dependent dioxygenase catalyzing the iterative oxidation of 5-methylcytosine(5mC),has been widely recognized to be an important regulato...TET2,a member of ten-eleven translocation(TET)family as a-ketoglutarate-and Fe2+-dependent dioxygenase catalyzing the iterative oxidation of 5-methylcytosine(5mC),has been widely recognized to be an important regulator for normal hematopoiesis especially myelopoiesis.Mutation and dysregulation of TET2 contribute to the development of multiple hematological malignancies.Recent studies reveal that TET2 also plays an important role in innate immune homeostasis by promoting DNA demethylation or independent of its enzymatic activity.Here,we focus on the functions of TET2 in the initiation and resolution of inflammation through epigenetic regulation and signaling network.In addition,we highlight regulation of TET2 at various molecular levels as well as the correlated inflammatory diseases,which will provide the insight to intervene in the pathological process caused by TET2 dysregulation.展开更多
Mitochondrial stress (mitostress) triggered by viral infection or mitochondrial dysfunction causes the release of mitochondrial DNA (mtDNA) into the cytosol and activates the cGAS-mediated innate immune response. The ...Mitochondrial stress (mitostress) triggered by viral infection or mitochondrial dysfunction causes the release of mitochondrial DNA (mtDNA) into the cytosol and activates the cGAS-mediated innate immune response. The regulation of mtDNA release upon mitostress remains uncharacterized. Here, we identified mitochondria-associated vaccinia virus-related kinase 2 (VRK2) as a key regulator of this process. VRK2 deficiency inhibited the induction of antiviral genes and caused earlier and higher mortality in mice after viral infection. Upon viral infection, VRK2 associated with voltage-dependent anion channel 1 (VDAC1) and promoted VDAC1 oligomerization and mtDNA release, leading to the cGAS-mediated innate immune response. VRK2 was also required for mtDNA release and cGAS-mediated innate immunity triggered by nonviral factors that cause Ca^(2+) overload but was not required for the cytosolic nucleic acid-triggered innate immune response. Thus, VRK2 plays a crucial role in the mtDNA-triggered innate immune response and may be a potential therapeutic target for infectious and autoimmune diseases associated with mtDNA release.展开更多
Exogenous RNA poses a continuous threat to genome stability and integrity across various organisms.Accumulating evidence reveals complex mechanisms underlying the cellular response to exogenous RNA,including endo-lyso...Exogenous RNA poses a continuous threat to genome stability and integrity across various organisms.Accumulating evidence reveals complex mechanisms underlying the cellular response to exogenous RNA,including endo-lysosomal degradation,RNA-dependent repression and innate immune clearance.Across a variety of mechanisms,the natural anti-sense RNAdependent defensive strategy has been utilized both as a powerful gene manipulation tool and gene therapy strategy named RNA-interference(RNAi).To optimize the efficiency of RNAi silencing,a comprehensive understanding of the whole life cycle of exogenous RNA,from cellular entry to its decay,is vital.In this paper,we review recent progress in comprehending the recognition and elimination of foreign RNA by cells,focusing on cellular entrance,intracellular transportation,and immune-inflammatory responses.By leveraging these insights,we highlight the potential implications of these insights for advancing RNA interference efficiency,underscore the need for future studies to elucidate the pathways and fates of various exogenous RNA forms,and provide foundational information for more efficient RNA delivery methods in both genetic manipulation and therapy in different organisms.展开更多
Hantaan virus(HTNV)is a rodent-borne virus that causes hemorrhagic fever with renal syndrome(HFRS),resulting in a high mortality rate of 15%.Interferons(IFNs)play a critical role in the anti-hantaviral immune response...Hantaan virus(HTNV)is a rodent-borne virus that causes hemorrhagic fever with renal syndrome(HFRS),resulting in a high mortality rate of 15%.Interferons(IFNs)play a critical role in the anti-hantaviral immune response,and IFN pretreatment efficiently restricts HTNV infection by triggering the expression of a series of IFNstimulated genes(ISGs)through the Janus kinase-signal transducer and activator of transcription 1(JAK-STAT)pathway.However,the tremendous amount of IFNs produced during late infection could not restrain HTNV replication,and the mechanism remains unclear.Here,we demonstrated that receptor-interacting protein kinase 3(RIPK3),a crucial molecule that mediates necroptosis,was activated by HTNV and contributed to hantavirus evasion of IFN responses by inhibiting STAT1 phosphorylation.RNA-seq analysis revealed the upregulation of multiple cell death-related genes after HTNV infection,with RIPK3 identified as a key modulator of viral replication.RIPK3 ablation significantly enhanced ISGs expression and restrained HTNV replication,without affecting the expression of pattern recognition receptors(PRRs)or the production of type I IFNs.Conversely,exogenously expressed RIPK3 compromised the host's antiviral response and facilitated HTNV replication.RIPK3^(-/-)mice also maintained a robust ability to clear HTNV with enhanced innate immune responses.Mechanistically,we found that RIPK3 could bind STAT1 and inhibit STAT1 phosphorylation dependent on the protein kinase domain(PKD)of RIPK3 but not its kinase activity.Overall,these observations demonstrated a noncanonical function of RIPK3 during viral infection and have elucidated a novel host innate immunity evasion strategy utilized by HTNV.展开更多
Chronic obstructive pulmonary disease(COPD)is a common chronic respiratory disease and the third leading cause of death worldwide.Developments in next-generation sequencing technology have improved microbiome analysis...Chronic obstructive pulmonary disease(COPD)is a common chronic respiratory disease and the third leading cause of death worldwide.Developments in next-generation sequencing technology have improved microbiome analysis,which is increasingly recognized as an important component of disease management.Similar to the gut,the lung is a biosphere containing billions of microbial communities.The lung microbiome plays an important role in regulating and maintaining the host immune system.The microbiome composition,metabolites of microorganisms,and the interactions between the lung microbiome and the host immunity profoundly affect the occurrence,development,treatment,and prognosis of COPD.In this review,we drew comparisons between the lung microbiome of healthy individuals and that of patients with COPD.Furthermore,we summarize the intrinsic interactions between the host and the overall lung microbiome,focusing on the underlying mechanisms linking the microbiome to the host innate and adaptive immune response pathways.Finally,we discuss the possibility of using the microbiome as a biomarker to determine the stage and prognosis of COPD and the feasibility of developing a novel,safe,and effective therapeutic target.展开更多
Interferon gamma-inducible protein 16(IFI16)senses DNA in the cytoplasm and the nucleus by using two tandem hematopoietic interferon-inducible nuclear(HIN)domains,HINa and HINb,through the cooperative assembly of IFI1...Interferon gamma-inducible protein 16(IFI16)senses DNA in the cytoplasm and the nucleus by using two tandem hematopoietic interferon-inducible nuclear(HIN)domains,HINa and HINb,through the cooperative assembly of IFI16 filaments on double-stranded DNA(dsDNA).The role of HINa in sensing DNA is not clearly understood.Here,we describe the crystal structure of the HINa domain in complex with DNA at 2.55A°resolution and provide the first insight into the mode of DNA binding by the HINa domain.The structure reveals the presence of two oligosaccharide/nucleotide-binding(OB)folds with a unique DNA-binding surface.HINa uses loop L45 of the canonical OB2 fold to bind to the DNA backbone.The dsDNA is recognized as two single strands of DNA.Interestingly,deletion of HINb compromises the ability of IFI16 to induce IFN-b,while HINa mutants impaired in DNAbinding enhance the production of IFN-b.These results shed light on the roles of IFI16 HIN domains in DNA recognition and innate immune responses.展开更多
Epididymitis can be caused by infectious and noninfectious etiological factors.While microbial infections are responsible for infectious epididymitis,the etiological factors contributing to noninfectious epididymitis ...Epididymitis can be caused by infectious and noninfectious etiological factors.While microbial infections are responsible for infectious epididymitis,the etiological factors contributing to noninfectious epididymitis remain to be defined.The present study demonstrated that damaged male germ cells(DMGCs)induce epididymitis in mice.Intraperitoneal injection of the alkylating agent busulfan damaged murine male germ cells.Epididymitis was observed in mice 4 weeks after the injection of busulfan and was characterized by massive macrophage infiltration.Epididymitis was coincident with an accumulation of DMGCs in the epididymis.In contrast,busulfan injection into mice lacking male germ cells did not induce epididymitis.DMGCs induced innate immune responses in epididymal epithelial cells(EECs),thereby upregulating the pro-inflammatory cytokines such as tumor necrosis factor-a(7/VF-a),interleukin-6(/L-6),and interleukin-ip(IL-ip) as well as the chemokines such as monocyte chemotactic protein-1(MCP-1),monocyte chemotactic protein-5(MCP-5),and chemokine ligand-10(CXCL10).These results suggest that male germ cell damage may induce noninfectious epididymitis through the induction of innate immune responses in EECs.These findings provide novel insights into the mechanisms underlying noninfectious epididymitis,which might aid in the diagnosis and treatment of the disease.展开更多
Toll-like receptor 3(TLR3)-mediated signaling is important for host defense against RNA virus.Upon viral RNA stimulation,toll and interleukin-1 receptor domain-containing adaptor inducing IFN-p(TRIF)is recruited to TL...Toll-like receptor 3(TLR3)-mediated signaling is important for host defense against RNA virus.Upon viral RNA stimulation,toll and interleukin-1 receptor domain-containing adaptor inducing IFN-p(TRIF)is recruited to TLR3 and then undergoes oligomerization,which is required for the recruitment of downstream molecules to transmit signals.Here,we identified zinc finger CCHC-type containing 3(ZCCHC3)as a positive regulator of TLR3-mediated signaling.Overexpression of ZCCHC3 promoted transcription of downstream antiviral genes stimulated by the synthetic TLR3 ligand poly(I:C).ZCCHC3-deficiency markedly inhibited TLR3-but not TLR4-mediated induction of type I interferons(IFNs)and proinflammatory cytokines.Zcc/7c3-/-mice were more resistant to poly(l:C)-but not lipopolysaccharide-induced inflammatory death.Mechanistically,ZCCHC3 promoted recruitment of TRIF to TLR3 after poly(l:C)stimulation.Our findings reveal that ZCCHC3 plays an important role in TLR3-mediated innate immune response by promoting the recruitment of TRIF to TLR3 after ligand stimulation.展开更多
基金supported partly by NIH Research Grants R01AR062207,R01AR061484,and R56AI100901,Disease Targeted Research Grants from the American College of Rheumatology Research and Education Foundation.
文摘p204 is a member of the interferon-inducible p200 family proteins in mice.The p200 family has been reported to be multifunctional regulators of cell proliferation,differentiation,apoptosis and senescence.Interferon-inducible protein 16(IFI16)is regarded as the human ortholog of p204 in several studies.This is possibly due to the similarity of their structures.However the consistency of their functions is still elusive.Currently,an emerging focus has been placed upon the role of the p200 proteins as sensors for microbial DNA in innate immune responses and provides new insights into infections as well as autoimmune diseases.This review specially focuses on IFI16 and p204,the member of p200 family in human and murine respectively,and their pathophysiological roles in innate immune responses,cell differentiation and proliferation.
文摘An ancient conflict between hosts and pathogens has driven the innate and adaptive arms of immunity.Knowledge about this interplay can not only help us identify biological mechanisms but also reveal pathogen vulnerabilities that can be leveraged therapeutically.The humoral response to SARS-CoV-2 infection has been the focus of intense research,and the role of the innate immune system has received significantly less attention.Here,we review current knowledge of the innate immune response to SARS-CoV-2 infection and the various means SARS-CoV-2 employs to evade innate defense systems.We also consider the role of innate immunity in SARS-CoV-2 vaccines and in the phenomenon of long COVID.
基金This work was supported by research funding from the National Key Research and Development Program of China(Grant Nos.2017YFA0505900 and 2017YFD0500300)the National Basic Research Programs of China(Grant No.2014CB74440)+3 种基金the National Natural Science Foundation of China(Grant Nos.81571536 and 81571954)the Beijing Natural Science Foundation(Grant No.5162021)the Strategic Priority Research Program of the Chinese Academy of Sciences(Grant No.XDPB03)the Youth Innovation Promotion Association CAS.
文摘The intracellular pathogen Mycobacterium tuberculosis(Mtb)can survive in the host and cause disease by interfering with a variety of cellular functions.The mammalian cell entry 2(mce2)operon of Mtb has been shown to contribute to tuberculosis pathogenicity.However,little is known about the regulatory roles of Mtb Mce2 family proteins towards host cellular functions.Here we show that the Mce2 family protein Mce2E suppressed the macrophage innate immune response and promoted epithelial cell proliferation.Mce2E inhibited activation of the extracellular signal-regulated kinase(ERK)and Jun N-terminal kinase(JNK)mitogen-activated protein kinase(MAPK)signaling pathways in a non-canonical D motif(a MAPK-docking motif)-dependent manner,leading to reduced expression of TNF and IL-6 in macrophages.Furthermore,Mce2E promoted proliferation of human lung epithelium-derived lung adenoma A549 cells by inhibiting K48-linked polyubiquitination of eEF1A1 in aβstrand region-dependent manner.In summary,Mce2E is a novel multifunctional Mtb virulence factor that regulates host cellular functions in a niche-dependent manner.Our data suggest a potential novel target for TB therapy.
基金supported by grants from the National Key R&D Program of China(2017YFA0505800,2016YFA0502102)the National Natural Science Foundation of China(31630045,31521091,91429304 and 31671465)+1 种基金the Fundamental Research Funds for the Central Universities(2042017kf0205,2042017kf0242)Wuhan University Experiment Technology Project Funding.
文摘MITA is a central adaptor in innate immune responses to DNA viruses.The mechanisms responsible for recruitment of downstream kinase TBK1 and the transcription factor IRF3 to MITA remains enigmatic.Here we identified ZDHHC11,a member of DHHC palmitoyl transferase family,as a positive regulator of DNA virus-triggered signaling.Overexpression of ZDHHC11 activated the IFN-βpromoter,while ZDHHC11-deficiency specifically impaired DNA virus HSV-1-induced transcription of downstream antiviral genes.Zdhhc11^(−/−)mice exhibited lower serum cytokine levels and higher lethality after HSV-1 infection.Mechanistically,ZDHHC11 facilitated the optimal recruitment of IRF3 to MITA.Our findings support an important role for ZDHHC11 in mediating MITA-dependent innate immune responses against DNA viruses.
文摘The disease coronavirus disease 2019(COVID-19)is a severe respiratory illness that has emerged as a devastating health problem worldwide.The disease outcome is heterogeneous,and severity is likely dependent on the immunity of infected individuals and comorbidities.Although symptoms of the disease are primarily associated with respiratory problems,additional infection or failure of other vital organs are being reported.Emerging reports suggest a quite common co-existence of gastrointestinal(GI)tract symptoms in addition to respiratory symptoms in many COVID-19 patients,and some patients show just the GI symptoms.The possible cause of the GI symptoms could be due to direct infection of the epithelial cells of the gut,which is supported by the fact that(1)The intestinal epithelium expresses a high level of angiotensin-converting enzyme-2 and transmembrane protease serine 2 protein that are required for the severe acute respiratory syndrome coronavirus 2(SARS-CoV-2)entry into the cells;(2)About half of the severe COVID-19 patients show viral RNA in their feces and various parts of the GI tract;and(3)SARS-CoV-2 can directly infect gut epithelial cells in vitro(gut epithelial cells and organoids)and in vivo(rhesus monkey).The GI tract seems to be a site of active innate and adaptive immune responses to SARS-CoV-2 as clinically,stool samples of COVID-19 patients possess proinflammatory cytokines(interleukin 8),calprotectin(neutrophils activity),and immunoglobulin A antibodies.In addition to direct immune activation by the virus,impairment of GI epithelium integrity can evoke immune response under the influence of systemic cytokines,hypoxia,and changes in gut microbiota(dysbiosis)due to infection of the respiratory system,which is confirmed by the observation that not all of the GI symptomatic patients are viral RNA positive.This review comprehensively summarizes the possible GI immunomodulation by SARS-CoV-2 that could lead to GI symptoms,their association with disease severity,and potential therapeutic interventions.
基金This work was supported by the National Nature Science Foundation of China(31672361)the National Key R&D Program of China(2019YFE0120400).
文摘The eicosanoid signaling pathway mediates insect immune reactions to a wide range of stimuli. This pathway begins with the biosynthesis of arachidonic acid (AA) from the hydrolysis of phospholipids catalyzed by phospholipase A_(2) (PLA_(2)). We report here that the PLA_(2) inhibitor, dexamethasone (DEX), impaired the innate immune response including nodulation, encapsulation, and melanization in Ostrinia furnacalis larvae, while AA partially reversed these effects of DEX. We cloned a full-length complementary DNA encoding a PLA_(2), designated as OfsPLA_(2), from O. furnacalis. The open reading frame of OfsPLA_(2) encodes a 195-amino acid residue protein with a 22-residue signal peptide. Sequence alignment analyses indicated that O. furnacalis PLA_(2) might be a Group III secretory PLA_(2). The highest transcript levels of OfsPLA_(2) were detected in the fat body, and its transcript levels increased dramatically after infection with Escherichia coli, Micrococcus luteus, or Beauveria bassiana. Recombinant OfsPLA_(2) significantly induced prophenoloxidase (PPO) activation in larval hemolymph in the presence of Ca^(2+) and encapsulation of agarose beads. Injection of recombinant OfsPLA_(2) into larvae resulted in increased transcript levels of attacin, defencin, and moricin-3 genes. Our results demonstrate the involvement of the eicosanoid signaling pathway in the innate immune response of O. furnacalis larvae and provide new information about the roles of O. furnacalis secretory PLA_(2) in activating PPO and antimicrobial peptide production.
文摘Evolving data show a variable expression of clinical neurological manifestations in patients suffering with coronavirus disease 2019(COVID-19)from early disease onset.The most frequent symptoms and signs are fatigue,dizziness,impaired consciousness,ageusia,anosmia,radicular pain,and headache,as well as others.Based on the high number of series of cases reported,there is evidence for the implication of the immune system in the pathological mechanism of COVID-19.Although the exact role of the immunological mechanism is not elucidated,two main mechanisms are suggested which implicate the direct effect of severe acute respiratory syndrome coronavirus 2 infection in the central nervous system and neuroinflammation.In the context of neurological manifestations associated with COVID-19,neuropsychiatric disorders show an exacerbation and are described by symptoms and signs such as depression,anxiety,mood alterations,psychosis,post-traumatic stress disorder,delirium,and cognitive impairment,which appear to be common in COVID-19 survivors.A worsened score on psychopathological measures is seen in those with a history of psychiatric comorbidities.We review the neuropsychiatric manifestations associated with COVID-19 and some critical aspects of the innate and adaptive immune system involved in mental health disorders occurring in COVID-19.
基金This study was supported by grants from the Ministry of Science and Technology(National Key Research and Development Program 2016YFA0502203,2016YFA0502201,2019YFA0110201,2019YFA0110203,2018YFE0204500,and 2018YFC1004601)the National Natural Science Foundation of China(91740111,81871232 and 31870881)the 1.3.5 Project of Disciplines of Excellence and National Clinical Research Center for Geriatrics(Z20201001),West China Hospital,Sichuan University.
文摘Activation of the TAK1 signalosome is crucial for mediating the innate immune response to pathogen invasion and is regulated by multiple layers of posttranslational modifications,including ubiquitination,SUMOylation,and phosphorylation;however,the underlying molecular mechanism is not fully understood.In this study,TRIM60 negatively regulated the formation and activation of the TAK1 signalosome.Deficiency of TRIM60 in macrophages led to enhanced MAPK and NF-κB activation,accompanied by elevated levels of proinflammatory cytokines but not IFN-I.Immunoprecipitation-mass spectrometry assays identified TAB2 as the target of TRIM60 for SUMOylation rather than ubiquitination,resulting in impaired formation of the TRAF6/TAB2/TAK1 complex and downstream MAPK and NF-κB pathways.The SUMOylation sites of TAB2 mediated by TRIM60 were identified as K329 and K562;substitution of these lysines with arginines abolished the SUMOylation of TAB2.In vivo experiments showed that TRIM60-deficient mice showed an elevated immune response to LPS-induced septic shock and L.monocytogenes infection.Our data reveal that SUMOylation of TAB2 mediated by TRIM60 is a novel mechanism for regulating the innate immune response,potentially paving the way for a new strategy to control antibacterial immune responses.
基金The study was supported by the National Natural Science Foundation of China(Nos.82103749,81773338,and 82173432)ChineseAcademy ofMedicalSciencesMedicine andHealthTechnology InnovationProject(No.2017-I2M-1-017)+1 种基金Natural Science Foundation of Jiangsu Province(No.BK20190144)the Nanjing Incubation Program for National Clinical Research Center(No.2019060001).
文摘Objective: This study was designed to evaluate whether p62/SQSTM1 (hereafter referred to as p62) is involved in the immune response of macrophages against challenge byCandida albicans (C. albicans).Methods: We cultured bone marrow-derived macrophages (BMDMs) to investigate the immune response to challenge byC. albicans. The p62 gene was knocked down by transfection with p62 small interfering RNA (siRNA) in the p62 siRNA group. BMDMs transfected with nonsense siRNA served as the negative control (NC) group. These two groups of BMDMs were challenged withC. albicans in vitro. We detected p62 expression through quantitative reverse transcription PCR and western blotting. The phagocytosis ability of BMDMs was evaluated by flow cytometry and microscopic examination using an Olympus FV1000 laser scanning confocal microscope. Moreover, we determined the level of reactive oxygen species (ROS) in BMDMs. The mRNA levels of proinflammatory cytokines were determined by quantitative reverse transcription PCR.Results: After stimulation byC. albicans, the relative expression of p62 mRNA was increased in a dose-dependent manner, the relative expression of p62 and the ratio of BMDMs toC. albicans is 1.893 ± 0.2156 (1:1,P < 0.05), 2.873 ± 0.4787 (1:3,P < 0.05) and 3.556 ± 0.2892 (1:5,P < 0.01). The p62 protein level was also increased. After transfection with p62 siRNA, the mRNA and protein levels of p62 were significantly decreased in BMDMs (P < 0.05). After 0.5, 1 and 2 hours of co-culture of BMDMs withC. albicans, flow cytometry showed that the phagocytosis rates ofC. albicans by BMDMs were significantly lower in the p62 siRNA group than in the NC group (39.70 ± 1.69%vs. 55.23 ± 0.72%, 46.70 ± 0.89%vs. 60.80 ± 1.78%, 51.90 ± 0.98%vs. 64.43 ± 2.0%, respectively, allP < 0.05). Consistent results were seen in the production of ROS (4269 ± 392.6vs. 13426 ± 1859.7, 4967 ± 721.2vs. 13687 ± 2611.2, 7647 ± 1950.0vs. 17719 ± 1814.2, respectively, allP < 0.05). The ROS levels were higher in BMDMs of the NC group than in BMDMs transfected with p62 siRNA at 0.5, 1, and 2 hours after treatment withC. albicans. BMDMs was co-cultured withC. albicans for 4 and 12 hours, the mRNA levels of interleukin-1β and interleukin-18 in NCs were also higher than p62 siRNA group, interleukin-1β: (6.14 ± 1.63vs. 12.12 ± 0.54, 8.81 ± 0.86vs. 26.2 ± 4.67, respectively, allP < 0.05), IL-18: (0.38 ± 0.02vs. 0.97 ± 0.06, 0.44 ± 0.02vs. 2.23 ± 0.46, respectively, allP < 0.05).Conclusion: p62 plays an important role in the process of phagocytosis in BMDMs challenged byC. albicans through ROS production and expression of proinflammatory cytokines.
基金the National Key Research and Development Program of China(2018YFC1200100,2018ZX10301403,2020YFC0842400)National Natural Science Foundation of China(82025001)+4 种基金Ministries of Science and Technology of China,Education of Guangdong Province(2020B1111330001,2020A111128008,2020B1111320003,2020A0505100063,2020KZDZX1158,B195001248,2020A1515010911)National Key Technology R&D Program(2018YFC1311900)Guangdong Science and Technology Foundation(2019B030316028)State Key Laboratory of Respiratory Disease(SKLRD-QN-201912 and SKLRD-Z-202007)Guangzhou Medical University High-level University Innovation Team Training Program(Guangzhou Medical University released[2017]No.159).
文摘The coronavirus disease 2019(COVID-19)pandemic caused by severe acute respiratory syndrome coronavirus 2(SARS-CoV-2)represents a major public health threat worldwide.Insight into protective and pathogenic aspects of SARS-CoV-2 immune responses is critical to work out effective therapeutics and develop vaccines for controlling the disease.Here,we review the present literature describing the innate and adaptive immune responses including innate immune cells,cytokine responses,antibody responses and T cell responses against SARS-CoV-2 in human infection,as well as in AEC2-humanized mouse infection.We also summarize the now known and unknown about the role of the SARS-CoV-2 immune responses.By better understanding the mechanisms that drive the immune responses,we can tailor treatment strategies at specific disease stages and improve our response to this worldwide public health threat.
基金supported in part by the National Key R&D Program of China(No.2018YFC0910600)the National Natural Science Foundation of China(Nos.62007026,81627807,11727813,81871397,81701853,91859109)+3 种基金the Fok Ying-Tong Education Foundation of China(No.161104)the Program for the Young Top-notch Talent of Shaanxi Province,the Research Fund for Young Star of Science and Technology in Shaanxi Province of China(No.2018KJXX-018)the Science and Technology Projects of Xi’an,China(No.201809170CX11JC12)the Natural Science Basic Research Plan in Shaanxi Province of China(No.2019JQ-201).
文摘Objective::In order to study the important role and molecular mechanism of Brevinin-2 family antimicrobial peptide Brevinin-2ISb in methicillin-resistant Staphylococcus aureus(MRSA)infection of Caenorhabditis(C.)elegans,and to find the optimal therapeutic concentration of Brevinin-2ISb.Methods::By using a C.elegans model and MRSA infection modelto study the therapeutic effect of different concentrations of Brevinin-2ISb on C.elegans.Real-time PCR was used for investigating the effect of Brevinin-2ISb on the downstream gene expression of DAF-2/DAF-16 innate immune pathway and the major virulence factor gene expression of MRSA.With protein activity tests to study the inhibitory effect of Brevinin-2ISb on MRSA virulence factor protein activity.Finally,laser confocal imaging was carried out to observe real-time expression and distribution of downstream antimicrobial proteins to further prove the effect of Brevinin-2ISb on the activation of DAF-2/DAF-16 pathway by in vivo imaging.All animal study procedures were approved by the Academic Committee at Xidian University and Xi’an Jiaotong University Animal Care and Use Committee,China(approval No.JGC201207)on July 15,2017.Results::Host immunity was largely enhanced by Brevinin-2ISb,and the expression of staphylococcal enterotoxin genes,as well as virulence factors,was suppressed by Brevinin-2ISb.Indeed,the expression of many C.elegans innate immune genes,including lys-7,spp-1,K05D8.5 and C29F3.7,was induced by Brevinin-2ISb.In particular,robust,sustained expression of the antibacterial gene lys-7 was observed after Brevinin-2ISb treatment,resulting in increased protein levels.These effects correlated with a reduction in the MRSA-mediated death of the C.elegans host.Low concentrations of Brevinin-2ISb exhibited very low hemolytic activity,and may play a positive role in host innate immunity.Specifically,activation of the DAF-2/DAF-16 pathway appears to be essential for immune activation in C.elegans treated with Brevinin-2ISb.Based on the evolutionary conservation of innate immune pathways,our results suggest that Brevinin-2ISb not only has strong antibacterial activity,but may also enhance the innate immune response in humans.This study demonstrates that Brevinin-2ISb-related peptides are potential candidates for the development of novel anti-inflammatory or anti-microbial drugs.Conclusion::Antimicrobial peptide Brevinin-2ISb effectively inhibits MRSA at low concentration.This antimicrobial peptide can prolong the life of MRSA-infected C.elegans,has very low hemolytic activity and inhibits the activity and expression of various MRSA virulence factors.More importantly,Brevinin-2ISb activated the expression of antimicrobial genes downstream of DAF-2/DAF-16,which enhanced the MRSA resistance of C.elegans.This peptide could be used as the basis for developing new drugs to replace antibiotics.
基金This work was supported by grants from the State Key R&D Program of China(2017YFA0505800,2016YFA0502102)the National Natural Science Foundation of China(Grant Nos.31830024 and 31630045).
文摘The cyclic GMP-AMP (cGAMP) synthase (cGAS) plays a critical role in host defense by sensing cytosollc DNA derived from microbial pathogens or mls-located cellular DNA.Upon DNA binding,cGAS utilizes GTP and ATP as substrates to synthesize cGAMP,leading to MITA-mediated innate immune response.In this study,we identified the phosphatase PPP6C as a negative regulator of cGASmediated innate immune response.PPP6C is constitutively associated with cGAS in un-stimulated cells.DNA virus infection causes rapid disassociation of PPP6C from cGAS,resulting in phosphorylation of human cGAS S435 or mouse cGAS S420 in its catalytic pocket.Mutation of this eerine residue of cGAS impairs its ability to synthesize cGAMP upon DNA virus infection.In vitro experiments indicate that S420-phosphorylated mcGAS has higher affinity to GTP and enzymatic activity.PPP6Cdeficiency promotes innate immune response to DNA virus in various cells.Our findings suggest that PPP6Cmediated dephosphorylation of a catalytic pocket serine residue of cGAS impairs its substrate binding activity and innate immune response,which provides a mechanism for keeping the DNA sensor cGAS inactive in the absence of infection to avoid autoimmune response.
基金We thank Dr.Bingjing Wang for helpful discussion.This work was supported by grants from the National Natural Science Foundation of China(81788101,81922032)CAMS Innovation Fund for Medical Sciences(2016-12M-1-003).
文摘TET2,a member of ten-eleven translocation(TET)family as a-ketoglutarate-and Fe2+-dependent dioxygenase catalyzing the iterative oxidation of 5-methylcytosine(5mC),has been widely recognized to be an important regulator for normal hematopoiesis especially myelopoiesis.Mutation and dysregulation of TET2 contribute to the development of multiple hematological malignancies.Recent studies reveal that TET2 also plays an important role in innate immune homeostasis by promoting DNA demethylation or independent of its enzymatic activity.Here,we focus on the functions of TET2 in the initiation and resolution of inflammation through epigenetic regulation and signaling network.In addition,we highlight regulation of TET2 at various molecular levels as well as the correlated inflammatory diseases,which will provide the insight to intervene in the pathological process caused by TET2 dysregulation.
基金supported by grants from the State Key R&D Program of China(2017YFA0505800)the National Natural Science Foundation of China(31830024,31922021,31771555,31630045,and 31801188)the CAMS Innovation Fund for Medical Sciences(2019-I2M-5-071).
文摘Mitochondrial stress (mitostress) triggered by viral infection or mitochondrial dysfunction causes the release of mitochondrial DNA (mtDNA) into the cytosol and activates the cGAS-mediated innate immune response. The regulation of mtDNA release upon mitostress remains uncharacterized. Here, we identified mitochondria-associated vaccinia virus-related kinase 2 (VRK2) as a key regulator of this process. VRK2 deficiency inhibited the induction of antiviral genes and caused earlier and higher mortality in mice after viral infection. Upon viral infection, VRK2 associated with voltage-dependent anion channel 1 (VDAC1) and promoted VDAC1 oligomerization and mtDNA release, leading to the cGAS-mediated innate immune response. VRK2 was also required for mtDNA release and cGAS-mediated innate immunity triggered by nonviral factors that cause Ca^(2+) overload but was not required for the cytosolic nucleic acid-triggered innate immune response. Thus, VRK2 plays a crucial role in the mtDNA-triggered innate immune response and may be a potential therapeutic target for infectious and autoimmune diseases associated with mtDNA release.
基金supported by funding from:the National Natural Science Foundation of China to YY(Project Number:32270558)to XC(Project Number:32270512)and to CW(Project number:32100382)+3 种基金Young Taishan Scholar Program of Shandong Province to YYNatural Science Foundation of Jiangsu Province(Project Number:BK20220268)the Program of Qilu Young Scholars of Shandong University to XCand the King Saud University,Saudi Arabia(Project number:RSP2023R7).
文摘Exogenous RNA poses a continuous threat to genome stability and integrity across various organisms.Accumulating evidence reveals complex mechanisms underlying the cellular response to exogenous RNA,including endo-lysosomal degradation,RNA-dependent repression and innate immune clearance.Across a variety of mechanisms,the natural anti-sense RNAdependent defensive strategy has been utilized both as a powerful gene manipulation tool and gene therapy strategy named RNA-interference(RNAi).To optimize the efficiency of RNAi silencing,a comprehensive understanding of the whole life cycle of exogenous RNA,from cellular entry to its decay,is vital.In this paper,we review recent progress in comprehending the recognition and elimination of foreign RNA by cells,focusing on cellular entrance,intracellular transportation,and immune-inflammatory responses.By leveraging these insights,we highlight the potential implications of these insights for advancing RNA interference efficiency,underscore the need for future studies to elucidate the pathways and fates of various exogenous RNA forms,and provide foundational information for more efficient RNA delivery methods in both genetic manipulation and therapy in different organisms.
基金This work was supported in whole or in part by the National Natural Science Foundation of China(82172272,31970148 and 82222367)the Key Research and Development Program of Shaanxi(2021ZDLSF01-05 and 2021ZDLSF01-02).
文摘Hantaan virus(HTNV)is a rodent-borne virus that causes hemorrhagic fever with renal syndrome(HFRS),resulting in a high mortality rate of 15%.Interferons(IFNs)play a critical role in the anti-hantaviral immune response,and IFN pretreatment efficiently restricts HTNV infection by triggering the expression of a series of IFNstimulated genes(ISGs)through the Janus kinase-signal transducer and activator of transcription 1(JAK-STAT)pathway.However,the tremendous amount of IFNs produced during late infection could not restrain HTNV replication,and the mechanism remains unclear.Here,we demonstrated that receptor-interacting protein kinase 3(RIPK3),a crucial molecule that mediates necroptosis,was activated by HTNV and contributed to hantavirus evasion of IFN responses by inhibiting STAT1 phosphorylation.RNA-seq analysis revealed the upregulation of multiple cell death-related genes after HTNV infection,with RIPK3 identified as a key modulator of viral replication.RIPK3 ablation significantly enhanced ISGs expression and restrained HTNV replication,without affecting the expression of pattern recognition receptors(PRRs)or the production of type I IFNs.Conversely,exogenously expressed RIPK3 compromised the host's antiviral response and facilitated HTNV replication.RIPK3^(-/-)mice also maintained a robust ability to clear HTNV with enhanced innate immune responses.Mechanistically,we found that RIPK3 could bind STAT1 and inhibit STAT1 phosphorylation dependent on the protein kinase domain(PKD)of RIPK3 but not its kinase activity.Overall,these observations demonstrated a noncanonical function of RIPK3 during viral infection and have elucidated a novel host innate immunity evasion strategy utilized by HTNV.
基金Three Talents One Team Project of The Joint Logistic Support Force,Grant/Award Number:2021-439National Key Research and Development Program of China,Grant/Award Number:No.2021YFC2302300The Project of High-level Innovative Talents of the Armed Forces,Grant/Award Number:2022QN07351。
文摘Chronic obstructive pulmonary disease(COPD)is a common chronic respiratory disease and the third leading cause of death worldwide.Developments in next-generation sequencing technology have improved microbiome analysis,which is increasingly recognized as an important component of disease management.Similar to the gut,the lung is a biosphere containing billions of microbial communities.The lung microbiome plays an important role in regulating and maintaining the host immune system.The microbiome composition,metabolites of microorganisms,and the interactions between the lung microbiome and the host immunity profoundly affect the occurrence,development,treatment,and prognosis of COPD.In this review,we drew comparisons between the lung microbiome of healthy individuals and that of patients with COPD.Furthermore,we summarize the intrinsic interactions between the host and the overall lung microbiome,focusing on the underlying mechanisms linking the microbiome to the host innate and adaptive immune response pathways.Finally,we discuss the possibility of using the microbiome as a biomarker to determine the stage and prognosis of COPD and the feasibility of developing a novel,safe,and effective therapeutic target.
基金supported by the National Natural Science Foundation of China(grant no.31570875,31330019,31200559,and 81590761)the Ministry of Science and Technology of China(grant no.2014CB910400 and 2013CB911103)+2 种基金the National Science and Technology Major Project of China(grant no.2013ZX10004-602)the Beijing Nova Program(grant no.Z141102001814020)Youth Innovation Promotion Association CAS,and the special project of Ebola virus research from the president foundation of Chinese Academy of Sciences.
文摘Interferon gamma-inducible protein 16(IFI16)senses DNA in the cytoplasm and the nucleus by using two tandem hematopoietic interferon-inducible nuclear(HIN)domains,HINa and HINb,through the cooperative assembly of IFI16 filaments on double-stranded DNA(dsDNA).The role of HINa in sensing DNA is not clearly understood.Here,we describe the crystal structure of the HINa domain in complex with DNA at 2.55A°resolution and provide the first insight into the mode of DNA binding by the HINa domain.The structure reveals the presence of two oligosaccharide/nucleotide-binding(OB)folds with a unique DNA-binding surface.HINa uses loop L45 of the canonical OB2 fold to bind to the DNA backbone.The dsDNA is recognized as two single strands of DNA.Interestingly,deletion of HINb compromises the ability of IFI16 to induce IFN-b,while HINa mutants impaired in DNAbinding enhance the production of IFN-b.These results shed light on the roles of IFI16 HIN domains in DNA recognition and innate immune responses.
基金grants from the CAMS Initiative for Innovative Medicine(No.2017-I2M-B&R-06 and No.2017-I2M-3-007)the Major State Basic Research Project of China(No.2016YFA0101001 and No.2018YFC1003902)+1 种基金the National Natural Science Foundation of China(No.81701430)the China Postdoctoral Science Foundation(No.2017M611931).
文摘Epididymitis can be caused by infectious and noninfectious etiological factors.While microbial infections are responsible for infectious epididymitis,the etiological factors contributing to noninfectious epididymitis remain to be defined.The present study demonstrated that damaged male germ cells(DMGCs)induce epididymitis in mice.Intraperitoneal injection of the alkylating agent busulfan damaged murine male germ cells.Epididymitis was observed in mice 4 weeks after the injection of busulfan and was characterized by massive macrophage infiltration.Epididymitis was coincident with an accumulation of DMGCs in the epididymis.In contrast,busulfan injection into mice lacking male germ cells did not induce epididymitis.DMGCs induced innate immune responses in epididymal epithelial cells(EECs),thereby upregulating the pro-inflammatory cytokines such as tumor necrosis factor-a(7/VF-a),interleukin-6(/L-6),and interleukin-ip(IL-ip) as well as the chemokines such as monocyte chemotactic protein-1(MCP-1),monocyte chemotactic protein-5(MCP-5),and chemokine ligand-10(CXCL10).These results suggest that male germ cell damage may induce noninfectious epididymitis through the induction of innate immune responses in EECs.These findings provide novel insights into the mechanisms underlying noninfectious epididymitis,which might aid in the diagnosis and treatment of the disease.
基金This work was supported by grants from the State Key R&D Program of China(2017YFA0505800 and 2016YFA0502102)the National Natural Science Foundation of China(31830024,31630045,and 31800728).
文摘Toll-like receptor 3(TLR3)-mediated signaling is important for host defense against RNA virus.Upon viral RNA stimulation,toll and interleukin-1 receptor domain-containing adaptor inducing IFN-p(TRIF)is recruited to TLR3 and then undergoes oligomerization,which is required for the recruitment of downstream molecules to transmit signals.Here,we identified zinc finger CCHC-type containing 3(ZCCHC3)as a positive regulator of TLR3-mediated signaling.Overexpression of ZCCHC3 promoted transcription of downstream antiviral genes stimulated by the synthetic TLR3 ligand poly(I:C).ZCCHC3-deficiency markedly inhibited TLR3-but not TLR4-mediated induction of type I interferons(IFNs)and proinflammatory cytokines.Zcc/7c3-/-mice were more resistant to poly(l:C)-but not lipopolysaccharide-induced inflammatory death.Mechanistically,ZCCHC3 promoted recruitment of TRIF to TLR3 after poly(l:C)stimulation.Our findings reveal that ZCCHC3 plays an important role in TLR3-mediated innate immune response by promoting the recruitment of TRIF to TLR3 after ligand stimulation.
