Nanomaterials that can sequentially respond to internal and external stimuli,functioning as a sequential gate,have great potential for targeting different aspects of antitumor immunity.Herein,we construct a mannose-mo...Nanomaterials that can sequentially respond to internal and external stimuli,functioning as a sequential gate,have great potential for targeting different aspects of antitumor immunity.Herein,we construct a mannose-modified,pH and reactive oxygen species(ROS) sequential-responsive,transformable dualimmunofunction nanoprodrug(MpRTNP).This nanoprodrug encapsulates a transforming growth factor-β(TGF-β) receptor inhibitor SD-208(MpRTNP@SD),to simultaneously alleviate the immunosuppressive effects of TGF-β and tumor-associated macrophages(TAMs).In the weakly acidic tumor microenvironment(TME),the vesicle-micelle morphology transformation occurs owing to the protonation of PC7A,which is accompanied by SD-208 release to inhibit cancer-associated fibroblasts and regulatory T cells.The transformed micelles then target TAMs via mannose receptor-media ted endocytosis.Upon laser irradiation,the thioketal linker is cleaved,releasing conjugated chlorin e6 and generating ROS,which facilitates TAM polarization.The PC7A^(+) segment activates the stimulator of the interferon gene in TAMs with elevated phosphorylation of TANK binding kinase 1 and interferon regulatory factor 3,and type I interferon secretion.MpRTNP@SD displays superior abscopal effects and robust antitumor immunity,as evidenced by increased CD8^(+)/CD4^(+) T cell infiltration and reduced regulatory T cell(Treg) ratios.Mouse survival time is prolonged after combination with the CD47 antibody.This study provides a novel strategy for potent antitumor immunotherapy through pH and ROS sequential-gated spatiotemporal regulation of the TME.展开更多
Innate immunity is critical for the control of virus infection and operates to restrict viral susceptibility and direct antiviral immunity for protection from acute or chronic viral-associated diseases including cance...Innate immunity is critical for the control of virus infection and operates to restrict viral susceptibility and direct antiviral immunity for protection from acute or chronic viral-associated diseases including cancer. RIG-I like receptors(RLRs) are cytosolic RNA helicases that function as pathogen recognition receptors to detect RNA pathogen associated molecular patterns(PAMPs) of virus infection. The RLRs include RIG-I, MDA5, and LGP2. They function to recognize and bind to PAMP motifs within viral RNA in a process that directs the RLR to trigger downstream signaling cascades that induce innate immunity that controls viral replication and spread. Products of RLR signaling also serve to modulate the adaptive immune response to infection. Recent studies have additionally connected RLRs to signaling cascades that impart inflammatory and apoptotic responses to virus infection. Viral evasion of RLR signaling supports viral outgrowth and pathogenesis, including the onset of viral-associated cancer.展开更多
The Lome Infection and Immunity Conference is one of five scientific meetings held during each month of February at the Cumberland resort in the picturesque seaside town of Lome,on the Great Ocean Road in Victoria(Aus...The Lome Infection and Immunity Conference is one of five scientific meetings held during each month of February at the Cumberland resort in the picturesque seaside town of Lome,on the Great Ocean Road in Victoria(Australia).The specific aim of the meeting is to bring together basic,clinical and translational researchers-those who examine microbes and their impact on the innate or adaptive immune response,researchers who study the mechanisms that regulate immune responses,and those who apply this knowledge to preventing and treating infectious and in”ammatory diseases.The average number of attendees is 220,with registrants appreciative of the welcoming and relaxed atmosphere(Fig.1).展开更多
Objective:Trained immunity of natural killer(NK)cells has shown great potential in the treatment of cancers by eliciting enhanced effector responses to restimulation by cytokines or cancer cells for long time periods ...Objective:Trained immunity of natural killer(NK)cells has shown great potential in the treatment of cancers by eliciting enhanced effector responses to restimulation by cytokines or cancer cells for long time periods after preactivation.However,the human NK cells responsible for the generation and maintenance of trained immunity are largely unknown.We hypothesized that heterogeneous human NK cells would respond differentially to stimulation with a combination of IL-12,IL-15,and IL-18,and that an NK cell subset might exist that is mainly responsible for the induction of trained immunity.On the basis of our hypothesis,we aimed to identify the subset from which cytokine-trained human NK cells originate and to explore possible regulatory targets for drug intervention.Methods:Flow cytometry assays were performed to analyze the functions of cytokine-trained NK cells and examine cell division and protein expression in NK cell subsets.Single-cell RNA sequencing(scRNA-seq)plus TotalSeq™technology was used to track the heterogeneity of NK cells during the induction of trained immunity.Results:Traditional developmental markers for peripheral NK cells were unable to identify the precursors of human NK cells with trained immunity.Therefore,we used scRNA-seq plus TotalSeq™technology to track the heterogeneity of NK cells during the induction of trained immunity and identified a unique cluster of CD57−NKG2A+EZH2+IFNG+MKI67+IL12R+IL15R+IL18R+NK cells.Enrichment and pseudotime trajectory analyses suggested that this cluster of NK cells contained the precursor of trained NK cells.We then used flow cytometry to further investigate the role of EZH2 in trained NK precursors and found that CD57−NKG2A+EZH2+NK cells had faster cell cycles and an enhanced trained phenotype,and EZH2 inhibition significantly impaired the induction of trained immunity in NK cells.These results suggested that EZH2 is a unique epigenetic marker of precursors of human NK cells with trained immunity.Conclusions:Our work revealed human NK heterogeneity in the induction of trained immunity,identified the precursor subset for trained NK cells,and demonstrated the critical role of EZH2 in the induction of trained immunity in human NK cells.展开更多
Severe Acute Respiratory Syndrome （SARS） is a deadly infectious disease caused by SARS Coronavirus （SARS-CoV）. Inactivated SARS-CoV has been explored as a vaccine against SARS-CoV. However, safe and potent adjuvan...Severe Acute Respiratory Syndrome （SARS） is a deadly infectious disease caused by SARS Coronavirus （SARS-CoV）. Inactivated SARS-CoV has been explored as a vaccine against SARS-CoV. However, safe and potent adjuvants, especially with more efficient and economical needle-free vaccination are alw needed more urgently in a pandemic. The development of a safe and effective mucosal adjuvant and vaccine ays for prevention of emergent infectious diseases such as SARS will be an important advancement. PIKA, a stabilized derivative of Poly （I：C）, was previously reported to be safe and potent as adjuvant in mouse models. In the present study, we demonstrated that the intraperitoneal and intranasal co-administration of inactivated SARS-CoV vaccine together with this improved Poly （I：C） derivative induced strong anti-SARS-CoV mucosal and systemic humoral immune responses with neutralizing activity against pseudotyped virus. Although intraperitoneal immunization of inactivated SARS-CoV vaccine alone could induce a certain level of neutralizing activity in serum as well as in mucosal sites, co-administration of inactivated SARS-CoV vaccine with PIKA as adjuvant could induce a much higher neutralizing activity. When intranasal immunization was used, PIKA was obligatorily for inducing neutralizing activity in serum as well as in mucosal sites and was correlated with both mucosal IgA and mucosal IgG response. Overall, PIKA could be a good mucosal adjuvant candidate for inactivated SARS-CoV vaccine for use in possible future pandemic.展开更多
INTRODUCTION An effective coordination of immune and non-immune cells is essential for generating optimal regional immunity to combat tumorigenesis and infection at barrier tissues such as lung.Regional immune structu...INTRODUCTION An effective coordination of immune and non-immune cells is essential for generating optimal regional immunity to combat tumorigenesis and infection at barrier tissues such as lung.Regional immune structures such as inducible bronchus-associated lymphoid tissue(iBALT)and tertiary lymphoid structure(TLS)play essential roles in modulating lung local immune responses.While the identification of iBALTs or TLS is generally dependent on conventional histology,it remains poorly understood how immune cells are spatiotemporally coordinated in the lung at single-cell resolution to effectively eliminate malignant cells and invading pathogens.Recently studies have revealed the presence of dendritic cell(DC)-T immunity hubs in human lung with close association with tumor immunotherapy response[1],antiviral immunity[2],and inflammation resolution[3].展开更多
In nature,plants are under attack by a range of pathogens.To cope with these pathogens,plants have evolved a sophisticated immune system,including pattern-triggered immunity(PTI)initiated by pattern recognition recept...In nature,plants are under attack by a range of pathogens.To cope with these pathogens,plants have evolved a sophisticated immune system,including pattern-triggered immunity(PTI)initiated by pattern recognition receptors on the cell surface and effector-triggered immunity(ETI)activated by intracellular nucleotide-binding and leucine-rich repeat receptors.In recent years,increasing evidence has demonstrated that organelles such as the chloroplast play crucial roles in complete activation of plant immunity.In this review,we focus on the chloroplast and summarize its role in regulating the activation of immune events,including influx of calcium(Ca^(2+)),accumulation of reactive oxygen species(ROS),biosynthesis of phytohormones,and expression of defense-related genes.Because information exchange between the chloroplast and the nucleus is very important during plant immunity,we also highlight the importance of chloroplast-nucleus communication via stromules in plant immunity.This review reveals the function of the chloroplast in maintaining the trade-off between plant growth and immunity,and expands our understanding of how chloroplasts enable complete activation of plant immunity.展开更多
In their natural habitats,bacteria thrive in densely populated environments(such as soil and the human gut)and compete with other microorganisms for ecological niches[1].Secretion systems enable bacteria to export pro...In their natural habitats,bacteria thrive in densely populated environments(such as soil and the human gut)and compete with other microorganisms for ecological niches[1].Secretion systems enable bacteria to export proteins into their surroundings and play key roles in interbacterial competition,development,nutrient acquisition,and virulence[2–4].Type VII secretion system b(T7SSb)has been primarily identified in low-G+C Firmicutes,which exhibit significant inter-and intraspecies heterogeneity in secreting putative toxin effectors.展开更多
Prof.Zhijian James Chen,a distinguished scientist in the field of innate immunity,has been honored with the 2025 Paul Ehrlich and Ludwig Darmstaedter Prize and the 2024 Albert Lasker Basic Medical Research Award for h...Prof.Zhijian James Chen,a distinguished scientist in the field of innate immunity,has been honored with the 2025 Paul Ehrlich and Ludwig Darmstaedter Prize and the 2024 Albert Lasker Basic Medical Research Award for his groundbreaking discovery of the enzyme cyclic guanosine monophosphate-adenosine monophosphate synthase(cGAS).His research has transformed the understanding of innate immune responses,particularly the role of cGAS as a cytosolic DNA sensor that triggers an interferon response.In this dialogue,Prof.Chen reflects on his research journey,from his initial exploration of ubiquitin and nuclear factor-kB(NF-kB)signaling to his discoveries of mitochondrial antiviral-signaling protein(MAVS)and cGAS,highlighting his lifelong interest in cell signaling and human diseases.The interview underscores the importance of perseverance and the pursuit of impactful research questions in scientific endeavors.This scholarly exchange offers a mentor-like perspective for aspiring scientists,encapsulating the essence of a successful career in biomedical research.展开更多
Lipid droplets(LDs)are intracellular organelles that can be induced and interact with phagosomes during the process of pathogen phagocytosis in macrophages.However,the function of LDs in phagocytosis remains elusive.H...Lipid droplets(LDs)are intracellular organelles that can be induced and interact with phagosomes during the process of pathogen phagocytosis in macrophages.However,the function of LDs in phagocytosis remains elusive.Here,we unveil the role of LDs in modulating phagosome formation via a fungal infection model.Specifically,LD accumulation restricted the degree of phagosome formation and protected macrophages from death.Mechanistically,LD formation competitively consumed the intracellular endoplasmic reticulum membrane and altered RAC1 translocation and GTPase activity,which resulted in limited phagosome formation in macrophages during fungal engulfment.Mice with Hilpda-deficient macrophages were more susceptible to the lethal sequelae of systemic infection with C.albicans.Notably,administration of the ATGL inhibitor atglistatin improved host outcomes in disseminated fungal infections.Taken together,our study elucidates the mechanism by which LDs control phagosome formation to prevent immune cell death and offers a potential drug target for the treatment of C.albicans infections.展开更多
While conventional chemical fungicides directly eliminate pathogens,plant immunity inducers activate or prime plant immunity.In recent years,considerable progress has been made in understanding the mechanisms of immun...While conventional chemical fungicides directly eliminate pathogens,plant immunity inducers activate or prime plant immunity.In recent years,considerable progress has been made in understanding the mechanisms of immune regulation in plants.The development and application of plant immunity inducers based on the principles of plant immunity represent a new field in plant protection research.In this review,we describe the mechanisms of plant immunity inducers in terms of plant immune system activation,summarize the various classes of reported plant immunity inducers(proteins,oligosaccharides,chemicals,and lipids),and review methods for the identification or synthesis of plant immunity inducers.The current situation,new strategies,and future prospects in the development and application of plant immunity inducers are also discussed.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
Follicular helper T （TFH） cells represent a distinct subset of CD4＋ helper T （TH） cells specialized in providing help to B cells. They are characterized by their unique transcriptional profile （Bcl6）, surface m...Follicular helper T （TFH） cells represent a distinct subset of CD4＋ helper T （TH） cells specialized in providing help to B cells. They are characterized by their unique transcriptional profile （Bcl6）, surface marker expression （CXCR5, PD-1, ICOS and CD4OL） and cytokine production pattern （IL-21 and IL-6）. TFH cells provide help to B cells both to form germinal centers （GCs） and to differentiate into memory B cells and plasma cells for generation of humoral responses. However, there is emerging evidence that implicates TFH cells in the development of various human pathologies, such as autoimmune diseases, immunodeficiency and lymphoma. This review focuses on the current progress in this area including mouse and human studies. A clearer understanding of the mechanisms of TFH cell-mediated immunity and pathology may be exploited for rational development of therapeutic strategies. Cellular＆ Molecular Immunology（2012） 9, 380-385; doi：10.1038/cmi.2012.26; published online 13 August 2012展开更多
Plant pathogens rely on effector proteins to suppress host innate immune responses and facilitate colonization.Although the Phytophthora sojae RxLR effector Avh241 promotes Phytophthora infection,the molecular basis o...Plant pathogens rely on effector proteins to suppress host innate immune responses and facilitate colonization.Although the Phytophthora sojae RxLR effector Avh241 promotes Phytophthora infection,the molecular basis of Avh241 virulence remains poorly understood.Here we identified non-race specific disease resistance 1(NDR1)-like proteins,the critical components in plant effector-triggered immunity(ETI)responses,as host targets of Avh241.Avh241 interacts with NDR1 in the plasma membrane and suppresses NDR1-participated ETI responses.Silencing of GmNDR1s increases the susceptibility of soybean to P.sojae infection,and overexpression of GmNDR1s reduces infection,which supports its positive role in plant immunity against P.sojae.Furthermore,we demonstrate that GmNDR1 interacts with itself,and Avh241 probably disrupts the self-association of GmNDR1.These data highlight an effective counter-defense mechanism by which a Phytophthora effector suppresses plant immune responses,likely by disturbing the function of NDR1 during infection.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
Mitogen-activated protein kinase(MAPK) cascades are highly conserved signaling modules that regulate plant immune responses. The Arabidopsis thaliana Raf-like MAPK kinase kinase ENHANCED DISEASE RESISTANCE1(EDR1) is a...Mitogen-activated protein kinase(MAPK) cascades are highly conserved signaling modules that regulate plant immune responses. The Arabidopsis thaliana Raf-like MAPK kinase kinase ENHANCED DISEASE RESISTANCE1(EDR1) is a key negative regulator of plant immunity that affects the protein levels of MKK4 and MKK5, two important MAPK cascade members, but the underlying mechanism is poorly understood. Here, genome-wide phosphorylation analysis demonstrated that the E3 ligase KEEP ON GOING(KEG) is phosphorylated in the edr1 mutant but not the wild type, suggesting that EDR1 negatively affects KEG phosphorylation. The identified phosphorylation sites in KEG appear to be important for its accumulation. The keg-4 mutant, a previously identified edr1 suppressor, enhances susceptibility to the powdery mildew pathogen Golovinomyces cichoracearum. In addition, MKK4 and MKK5 protein levels are reduced in the keg-4 mutant. Furthermore,we demonstrate that MKK4 and MKK5 associate with full-length KEG, but not with truncated KEG-RK or KEG-RKA, and that KEG ubiquitinates and mediates the degradation of MKK4 and MKK5. Taken together, these results indicate that MKK4 and MKK5 protein levels are regulated by KEG via ubiquitination, uncovering a mechanism by which plants finetune immune responses by regulating the homeostasis of key MAPK cascade members via ubiquitination and degradation.展开更多
Alternative splicing(AS)of pre-mRNAs increases transcriptome and proteome diversity,regulates gene expression through multiple mechanisms,and plays important roles in plant development and stress responses.However,the...Alternative splicing(AS)of pre-mRNAs increases transcriptome and proteome diversity,regulates gene expression through multiple mechanisms,and plays important roles in plant development and stress responses.However,the prevalence of genome-wide plant AS changes during infection and the mechanisms by which pathogens modulate AS remain poorly understood.Here,we examined the global AS changes in tomato leaves infected with Phytophthora infestans,the infamous Irish famine pathogen.We show that more than 2000 genes exhibiting significant changes in AS are not differentially expressed,indicating that AS is a distinct layer of transcriptome reprogramming during plant-pathogen interactions.Furthermore,our results show that P.infestans subverts host immunity by repressing the AS of positive regulators of plant immunity and promoting the AS of susceptibility factors.To study the underlying mechanism,we established a luminescence-based AS reporter system in Nicotiana benthamiana to screen pathogen effectors modulating plant AS.We identified nine splicing regulatory effectors(SREs)from 87 P.infestans effectors.Further studies revealed that SRE3 physically binds U1-70K to manipulate the plant AS machinery and subsequently modulates AS-mediated plant immunity.Our study not only unveils genome-wide plant AS reprogramming during infection but also establishes a novel AS screening tool to identify SREs from a wide range of plant pathogens,providing opportunities to understand the splicing regulatory mechanisms through which pathogens subvert plant immunity.展开更多
Plants employ receptor-like kinases (RLKs)and receptor-like proteins for rapid recognition of invading pathogens,and RLKs then transmit signals to receptor-like cytoplasmic kinases (RLCKs)to activate immune responses....Plants employ receptor-like kinases (RLKs)and receptor-like proteins for rapid recognition of invading pathogens,and RLKs then transmit signals to receptor-like cytoplasmic kinases (RLCKs)to activate immune responses.RLKs are under fine regulation mediated by subcellular trafficking,which contributes to proper activation of plant immunity.In this study,we show that Arabidopsisthaliana RECEPTOR-LIKE KINASE 902 (RLK902)plays important roles in resistance to the bacterial pathogen Pseudomonas syringae, but not to the fungal powdery mildew pathogen Golovinomyces cichoracearum.RLK902 localizes at the plasma membrane and associates with ENHANCED DISEASE RESISTANCE 4 (EDR4),a protein involved in clathrin-mediated trafficking pathways.EDR4 and CLATHRIN HEAVY CHAIN 2 (CHC2)regulate the subcellular trafficking and accumulation of RLK902 protein.Furthermore,we found that RLKg02 directly associates with the RLCK BRASSINOSTEROID-SIGNALING KINASE1 (BSK1),a key component of plant immunity,but not with other members of the FLAGELLIN SENSING 2 immune complex.RLK902 phosphorylates BSK1,and its Ser-230 is a key phosphorylation site critical for RLK902-mediated defense signaling. Taken together,our data indicate that EDR4 regulates plant immunity by modulating the subcellular trafficking and protein accumulation of RLK902,and that RLK902 transmits immune signals by phosphorylating BSK1.展开更多
基金supported by National Natural Science Foundation of China(Nos.52103190 and 52103191)Special Program for Supporting Innovative Youth Talent Teams(No.32320683)+1 种基金Start-up Grant(Nos.32340311 and 35220151) from Zhengzhou UniversityNatural Science Foundation of Henan Province(No.242300420127)。
文摘Nanomaterials that can sequentially respond to internal and external stimuli,functioning as a sequential gate,have great potential for targeting different aspects of antitumor immunity.Herein,we construct a mannose-modified,pH and reactive oxygen species(ROS) sequential-responsive,transformable dualimmunofunction nanoprodrug(MpRTNP).This nanoprodrug encapsulates a transforming growth factor-β(TGF-β) receptor inhibitor SD-208(MpRTNP@SD),to simultaneously alleviate the immunosuppressive effects of TGF-β and tumor-associated macrophages(TAMs).In the weakly acidic tumor microenvironment(TME),the vesicle-micelle morphology transformation occurs owing to the protonation of PC7A,which is accompanied by SD-208 release to inhibit cancer-associated fibroblasts and regulatory T cells.The transformed micelles then target TAMs via mannose receptor-media ted endocytosis.Upon laser irradiation,the thioketal linker is cleaved,releasing conjugated chlorin e6 and generating ROS,which facilitates TAM polarization.The PC7A^(+) segment activates the stimulator of the interferon gene in TAMs with elevated phosphorylation of TANK binding kinase 1 and interferon regulatory factor 3,and type I interferon secretion.MpRTNP@SD displays superior abscopal effects and robust antitumor immunity,as evidenced by increased CD8^(+)/CD4^(+) T cell infiltration and reduced regulatory T cell(Treg) ratios.Mouse survival time is prolonged after combination with the CD47 antibody.This study provides a novel strategy for potent antitumor immunotherapy through pH and ROS sequential-gated spatiotemporal regulation of the TME.
基金supported by National Institutes of Health grants AI083019, AI104002, and AI88778
文摘Innate immunity is critical for the control of virus infection and operates to restrict viral susceptibility and direct antiviral immunity for protection from acute or chronic viral-associated diseases including cancer. RIG-I like receptors(RLRs) are cytosolic RNA helicases that function as pathogen recognition receptors to detect RNA pathogen associated molecular patterns(PAMPs) of virus infection. The RLRs include RIG-I, MDA5, and LGP2. They function to recognize and bind to PAMP motifs within viral RNA in a process that directs the RLR to trigger downstream signaling cascades that induce innate immunity that controls viral replication and spread. Products of RLR signaling also serve to modulate the adaptive immune response to infection. Recent studies have additionally connected RLRs to signaling cascades that impart inflammatory and apoptotic responses to virus infection. Viral evasion of RLR signaling supports viral outgrowth and pathogenesis, including the onset of viral-associated cancer.
文摘The Lome Infection and Immunity Conference is one of five scientific meetings held during each month of February at the Cumberland resort in the picturesque seaside town of Lome,on the Great Ocean Road in Victoria(Australia).The specific aim of the meeting is to bring together basic,clinical and translational researchers-those who examine microbes and their impact on the innate or adaptive immune response,researchers who study the mechanisms that regulate immune responses,and those who apply this knowledge to preventing and treating infectious and in”ammatory diseases.The average number of attendees is 220,with registrants appreciative of the welcoming and relaxed atmosphere(Fig.1).
基金This work was supported by grants from The National Key R&D Program(Grant Nos.2018YFC1313400,2018YFC1313000,and 2018YFC1313002)The National Natural Science Foundation of China(Grant Nos.81872166,U20A20375,31600705,81974416,and 81702405)The Tianjin Natural Science Foundation(Grant No.17JCQNJC09000)。
文摘Objective:Trained immunity of natural killer(NK)cells has shown great potential in the treatment of cancers by eliciting enhanced effector responses to restimulation by cytokines or cancer cells for long time periods after preactivation.However,the human NK cells responsible for the generation and maintenance of trained immunity are largely unknown.We hypothesized that heterogeneous human NK cells would respond differentially to stimulation with a combination of IL-12,IL-15,and IL-18,and that an NK cell subset might exist that is mainly responsible for the induction of trained immunity.On the basis of our hypothesis,we aimed to identify the subset from which cytokine-trained human NK cells originate and to explore possible regulatory targets for drug intervention.Methods:Flow cytometry assays were performed to analyze the functions of cytokine-trained NK cells and examine cell division and protein expression in NK cell subsets.Single-cell RNA sequencing(scRNA-seq)plus TotalSeq™technology was used to track the heterogeneity of NK cells during the induction of trained immunity.Results:Traditional developmental markers for peripheral NK cells were unable to identify the precursors of human NK cells with trained immunity.Therefore,we used scRNA-seq plus TotalSeq™technology to track the heterogeneity of NK cells during the induction of trained immunity and identified a unique cluster of CD57−NKG2A+EZH2+IFNG+MKI67+IL12R+IL15R+IL18R+NK cells.Enrichment and pseudotime trajectory analyses suggested that this cluster of NK cells contained the precursor of trained NK cells.We then used flow cytometry to further investigate the role of EZH2 in trained NK precursors and found that CD57−NKG2A+EZH2+NK cells had faster cell cycles and an enhanced trained phenotype,and EZH2 inhibition significantly impaired the induction of trained immunity in NK cells.These results suggested that EZH2 is a unique epigenetic marker of precursors of human NK cells with trained immunity.Conclusions:Our work revealed human NK heterogeneity in the induction of trained immunity,identified the precursor subset for trained NK cells,and demonstrated the critical role of EZH2 in the induction of trained immunity in human NK cells.
基金supported by the National Natural Science Foundation of China (30670097)National Basic Research Program of China (973 Program) (2005CB522903)+1 种基金National Key R&D Program (2007BAI28B04)National S&T Major Project on Major Infectious Diseases (2008ZX10001-010)from the Ministry of Science and Technology of the People’s Republic of China
文摘Severe Acute Respiratory Syndrome （SARS） is a deadly infectious disease caused by SARS Coronavirus （SARS-CoV）. Inactivated SARS-CoV has been explored as a vaccine against SARS-CoV. However, safe and potent adjuvants, especially with more efficient and economical needle-free vaccination are alw needed more urgently in a pandemic. The development of a safe and effective mucosal adjuvant and vaccine ays for prevention of emergent infectious diseases such as SARS will be an important advancement. PIKA, a stabilized derivative of Poly （I：C）, was previously reported to be safe and potent as adjuvant in mouse models. In the present study, we demonstrated that the intraperitoneal and intranasal co-administration of inactivated SARS-CoV vaccine together with this improved Poly （I：C） derivative induced strong anti-SARS-CoV mucosal and systemic humoral immune responses with neutralizing activity against pseudotyped virus. Although intraperitoneal immunization of inactivated SARS-CoV vaccine alone could induce a certain level of neutralizing activity in serum as well as in mucosal sites, co-administration of inactivated SARS-CoV vaccine with PIKA as adjuvant could induce a much higher neutralizing activity. When intranasal immunization was used, PIKA was obligatorily for inducing neutralizing activity in serum as well as in mucosal sites and was correlated with both mucosal IgA and mucosal IgG response. Overall, PIKA could be a good mucosal adjuvant candidate for inactivated SARS-CoV vaccine for use in possible future pandemic.
基金supported by Grants from the National Key R&D Program of China(2023YFA1801400)National Natural Science Foundation of China(92374115 and 82388201).
文摘INTRODUCTION An effective coordination of immune and non-immune cells is essential for generating optimal regional immunity to combat tumorigenesis and infection at barrier tissues such as lung.Regional immune structures such as inducible bronchus-associated lymphoid tissue(iBALT)and tertiary lymphoid structure(TLS)play essential roles in modulating lung local immune responses.While the identification of iBALTs or TLS is generally dependent on conventional histology,it remains poorly understood how immune cells are spatiotemporally coordinated in the lung at single-cell resolution to effectively eliminate malignant cells and invading pathogens.Recently studies have revealed the presence of dendritic cell(DC)-T immunity hubs in human lung with close association with tumor immunotherapy response[1],antiviral immunity[2],and inflammation resolution[3].
基金supported by grants from the Natural Science Foundation of Fujian Province,China(grant no.2024J09022)the National Natural Science Foundation of China(grant no.32370302)the Open Fund of Fujian Provincial Key Laboratory of Eco-Industrial Green Technology(grant no.WYKF-EIGT2022-6).
文摘In nature,plants are under attack by a range of pathogens.To cope with these pathogens,plants have evolved a sophisticated immune system,including pattern-triggered immunity(PTI)initiated by pattern recognition receptors on the cell surface and effector-triggered immunity(ETI)activated by intracellular nucleotide-binding and leucine-rich repeat receptors.In recent years,increasing evidence has demonstrated that organelles such as the chloroplast play crucial roles in complete activation of plant immunity.In this review,we focus on the chloroplast and summarize its role in regulating the activation of immune events,including influx of calcium(Ca^(2+)),accumulation of reactive oxygen species(ROS),biosynthesis of phytohormones,and expression of defense-related genes.Because information exchange between the chloroplast and the nucleus is very important during plant immunity,we also highlight the importance of chloroplast-nucleus communication via stromules in plant immunity.This review reveals the function of the chloroplast in maintaining the trade-off between plant growth and immunity,and expands our understanding of how chloroplasts enable complete activation of plant immunity.
基金supported by the National Natural Science Foundation of China(82225028,82172287,32171265,31900879,and 32370185)the National Key Research and Development Program of China(2021YFC2301403)+1 种基金the high-level personnel introduction grant form Fujian Normal University(Z0210509)the Natural Science Foundation of Fujian Province(2023J011797 and 2024J010025).
文摘In their natural habitats,bacteria thrive in densely populated environments(such as soil and the human gut)and compete with other microorganisms for ecological niches[1].Secretion systems enable bacteria to export proteins into their surroundings and play key roles in interbacterial competition,development,nutrient acquisition,and virulence[2–4].Type VII secretion system b(T7SSb)has been primarily identified in low-G+C Firmicutes,which exhibit significant inter-and intraspecies heterogeneity in secreting putative toxin effectors.
文摘Prof.Zhijian James Chen,a distinguished scientist in the field of innate immunity,has been honored with the 2025 Paul Ehrlich and Ludwig Darmstaedter Prize and the 2024 Albert Lasker Basic Medical Research Award for his groundbreaking discovery of the enzyme cyclic guanosine monophosphate-adenosine monophosphate synthase(cGAS).His research has transformed the understanding of innate immune responses,particularly the role of cGAS as a cytosolic DNA sensor that triggers an interferon response.In this dialogue,Prof.Chen reflects on his research journey,from his initial exploration of ubiquitin and nuclear factor-kB(NF-kB)signaling to his discoveries of mitochondrial antiviral-signaling protein(MAVS)and cGAS,highlighting his lifelong interest in cell signaling and human diseases.The interview underscores the importance of perseverance and the pursuit of impactful research questions in scientific endeavors.This scholarly exchange offers a mentor-like perspective for aspiring scientists,encapsulating the essence of a successful career in biomedical research.
基金supported by grants from the National Natural Science Foundation of China(82321002,32230033 and 81930039 to CG)the National Key Research and Development Program of China(2021YFC2300603 and 2023YFC2306102 to CG)supported by the Future Scholar Program of Shandong University(21510082364125).
文摘Lipid droplets(LDs)are intracellular organelles that can be induced and interact with phagosomes during the process of pathogen phagocytosis in macrophages.However,the function of LDs in phagocytosis remains elusive.Here,we unveil the role of LDs in modulating phagosome formation via a fungal infection model.Specifically,LD accumulation restricted the degree of phagosome formation and protected macrophages from death.Mechanistically,LD formation competitively consumed the intracellular endoplasmic reticulum membrane and altered RAC1 translocation and GTPase activity,which resulted in limited phagosome formation in macrophages during fungal engulfment.Mice with Hilpda-deficient macrophages were more susceptible to the lethal sequelae of systemic infection with C.albicans.Notably,administration of the ATGL inhibitor atglistatin improved host outcomes in disseminated fungal infections.Taken together,our study elucidates the mechanism by which LDs control phagosome formation to prevent immune cell death and offers a potential drug target for the treatment of C.albicans infections.
基金supported by the National Natural Science Foundation of China(31721004,32001882)the Natural Science Foundation of Jiangsu Province(BK20190520)+1 种基金the China Post-doctoral Science Foundation(2018 M640496)the National Postdoctoral Program for Innovative Talents(BX20180142).
文摘While conventional chemical fungicides directly eliminate pathogens,plant immunity inducers activate or prime plant immunity.In recent years,considerable progress has been made in understanding the mechanisms of immune regulation in plants.The development and application of plant immunity inducers based on the principles of plant immunity represent a new field in plant protection research.In this review,we describe the mechanisms of plant immunity inducers in terms of plant immune system activation,summarize the various classes of reported plant immunity inducers(proteins,oligosaccharides,chemicals,and lipids),and review methods for the identification or synthesis of plant immunity inducers.The current situation,new strategies,and future prospects in the development and application of plant immunity inducers are also discussed.
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.
文摘Follicular helper T （TFH） cells represent a distinct subset of CD4＋ helper T （TH） cells specialized in providing help to B cells. They are characterized by their unique transcriptional profile （Bcl6）, surface marker expression （CXCR5, PD-1, ICOS and CD4OL） and cytokine production pattern （IL-21 and IL-6）. TFH cells provide help to B cells both to form germinal centers （GCs） and to differentiate into memory B cells and plasma cells for generation of humoral responses. However, there is emerging evidence that implicates TFH cells in the development of various human pathologies, such as autoimmune diseases, immunodeficiency and lymphoma. This review focuses on the current progress in this area including mouse and human studies. A clearer understanding of the mechanisms of TFH cell-mediated immunity and pathology may be exploited for rational development of therapeutic strategies. Cellular＆ Molecular Immunology（2012） 9, 380-385; doi：10.1038/cmi.2012.26; published online 13 August 2012
基金supported by the Natural ScienceFoundation of Jiangsu Province(BK20190520)the NationalNatural Science Foundation of China(31721004,32001882)the National Postdoctoral Program for Innovative Talents(BX20180142)。
文摘Plant pathogens rely on effector proteins to suppress host innate immune responses and facilitate colonization.Although the Phytophthora sojae RxLR effector Avh241 promotes Phytophthora infection,the molecular basis of Avh241 virulence remains poorly understood.Here we identified non-race specific disease resistance 1(NDR1)-like proteins,the critical components in plant effector-triggered immunity(ETI)responses,as host targets of Avh241.Avh241 interacts with NDR1 in the plasma membrane and suppresses NDR1-participated ETI responses.Silencing of GmNDR1s increases the susceptibility of soybean to P.sojae infection,and overexpression of GmNDR1s reduces infection,which supports its positive role in plant immunity against P.sojae.Furthermore,we demonstrate that GmNDR1 interacts with itself,and Avh241 probably disrupts the self-association of GmNDR1.These data highlight an effective counter-defense mechanism by which a Phytophthora effector suppresses plant immune responses,likely by disturbing the function of NDR1 during infection.
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 (31761133017 and 31525019) to D.T。
文摘Mitogen-activated protein kinase(MAPK) cascades are highly conserved signaling modules that regulate plant immune responses. The Arabidopsis thaliana Raf-like MAPK kinase kinase ENHANCED DISEASE RESISTANCE1(EDR1) is a key negative regulator of plant immunity that affects the protein levels of MKK4 and MKK5, two important MAPK cascade members, but the underlying mechanism is poorly understood. Here, genome-wide phosphorylation analysis demonstrated that the E3 ligase KEEP ON GOING(KEG) is phosphorylated in the edr1 mutant but not the wild type, suggesting that EDR1 negatively affects KEG phosphorylation. The identified phosphorylation sites in KEG appear to be important for its accumulation. The keg-4 mutant, a previously identified edr1 suppressor, enhances susceptibility to the powdery mildew pathogen Golovinomyces cichoracearum. In addition, MKK4 and MKK5 protein levels are reduced in the keg-4 mutant. Furthermore,we demonstrate that MKK4 and MKK5 associate with full-length KEG, but not with truncated KEG-RK or KEG-RKA, and that KEG ubiquitinates and mediates the degradation of MKK4 and MKK5. Taken together, these results indicate that MKK4 and MKK5 protein levels are regulated by KEG via ubiquitination, uncovering a mechanism by which plants finetune immune responses by regulating the homeostasis of key MAPK cascade members via ubiquitination and degradation.
基金the Chinese National Science Fund(31901862,31772144,31721004)Natural Science Foundation of Jiangsu Province(SBK2019040604)+1 种基金China Postdoctoral Science Foundation(2018M640494)the Fundamental Research Funds for the Central Uni-versities(JCQY201904,KYXK202010).
文摘Alternative splicing(AS)of pre-mRNAs increases transcriptome and proteome diversity,regulates gene expression through multiple mechanisms,and plays important roles in plant development and stress responses.However,the prevalence of genome-wide plant AS changes during infection and the mechanisms by which pathogens modulate AS remain poorly understood.Here,we examined the global AS changes in tomato leaves infected with Phytophthora infestans,the infamous Irish famine pathogen.We show that more than 2000 genes exhibiting significant changes in AS are not differentially expressed,indicating that AS is a distinct layer of transcriptome reprogramming during plant-pathogen interactions.Furthermore,our results show that P.infestans subverts host immunity by repressing the AS of positive regulators of plant immunity and promoting the AS of susceptibility factors.To study the underlying mechanism,we established a luminescence-based AS reporter system in Nicotiana benthamiana to screen pathogen effectors modulating plant AS.We identified nine splicing regulatory effectors(SREs)from 87 P.infestans effectors.Further studies revealed that SRE3 physically binds U1-70K to manipulate the plant AS machinery and subsequently modulates AS-mediated plant immunity.Our study not only unveils genome-wide plant AS reprogramming during infection but also establishes a novel AS screening tool to identify SREs from a wide range of plant pathogens,providing opportunities to understand the splicing regulatory mechanisms through which pathogens subvert plant immunity.
文摘Plants employ receptor-like kinases (RLKs)and receptor-like proteins for rapid recognition of invading pathogens,and RLKs then transmit signals to receptor-like cytoplasmic kinases (RLCKs)to activate immune responses.RLKs are under fine regulation mediated by subcellular trafficking,which contributes to proper activation of plant immunity.In this study,we show that Arabidopsisthaliana RECEPTOR-LIKE KINASE 902 (RLK902)plays important roles in resistance to the bacterial pathogen Pseudomonas syringae, but not to the fungal powdery mildew pathogen Golovinomyces cichoracearum.RLK902 localizes at the plasma membrane and associates with ENHANCED DISEASE RESISTANCE 4 (EDR4),a protein involved in clathrin-mediated trafficking pathways.EDR4 and CLATHRIN HEAVY CHAIN 2 (CHC2)regulate the subcellular trafficking and accumulation of RLK902 protein.Furthermore,we found that RLKg02 directly associates with the RLCK BRASSINOSTEROID-SIGNALING KINASE1 (BSK1),a key component of plant immunity,but not with other members of the FLAGELLIN SENSING 2 immune complex.RLK902 phosphorylates BSK1,and its Ser-230 is a key phosphorylation site critical for RLK902-mediated defense signaling. Taken together,our data indicate that EDR4 regulates plant immunity by modulating the subcellular trafficking and protein accumulation of RLK902,and that RLK902 transmits immune signals by phosphorylating BSK1.
