As computer technology continues to advance,factories have increasingly higher demands for detecting defects.However,detecting defects in a plant environment remains a challenging task due to the presence of complex b...As computer technology continues to advance,factories have increasingly higher demands for detecting defects.However,detecting defects in a plant environment remains a challenging task due to the presence of complex backgrounds and defects of varying shapes and sizes.To address this issue,this paper proposes YOLO-DD,a defect detectionmodel based on YOLOv5 that is effective and robust.To improve the feature extraction process and better capture global information,the vanilla YOLOv5 is augmented with a new module called Relative-Distance-Aware Transformer(RDAT).Additionally,an Information Gap Filling Strategy(IGFS)is proposed to improve the fusion of features at different scales.The classic lightweight attention mechanism Squeeze-and-Excitation(SE)module is also incorporated into the neck section to enhance feature expression and improve the model’s performance.Experimental results on the NEU-DET dataset demonstrate that YOLO-DDachieves competitive results compared to state-of-the-art methods,with a 2.0% increase in accuracy compared to the original YOLOv5,achieving 82.41% accuracy and38.25FPS(framesper second).Themodel is also testedon a self-constructed fabric defect dataset,and the results show that YOLO-DD is more stable and has higher accuracy than the original YOLOv5,demonstrating its stability and generalization ability.The high efficiency of YOLO-DD enables it to meet the requirements of industrial high accuracy and real-time detection.展开更多
In the post-genomics era, reliable phenotypes are considered the bottleneck for unraveling the genetic control over the biology of interest. Phenotyping resistance response of roots to infection by soilborne pathogen ...In the post-genomics era, reliable phenotypes are considered the bottleneck for unraveling the genetic control over the biology of interest. Phenotyping resistance response of roots to infection by soilborne pathogen is more challenging compared to that of plant aerial parts. In additional to the hidden nature and small stature of fine roots where infection occurs, extra obstacles exist for rosaceae tree crops such as apple. Due to self-incompatible reproduction and high-level heterozygosity of apple genome, genetically identical apple plants cannot be produced through apple seed germination. Here we report an established phenotyping protocol which includes a streamlined tissue culture procedure for micropropagation of uniform apple plants, standardized inoculation procedure using Pythium ultimum, and multilayered evaluating methods on apple root resistance traits. Because of the implementation of tissue culture based micropropagation procedure, constant availability of the uniform plants with defined genetic background, equivalent age and non-contaminated roots overcame a longstanding barrier of systematic and detailed phenotypic characterization of apple root resistance traits. Repeated infection assays by root-dipping inoculation demonstrated the reproducible and wide-range plant survival rates, from single-digit to over 90% survived plants for a given genotype. Genotype-specific values due to P. ultimum inoculation on shoot and root biomass reduction, maximum root lengths, leaf number and cumulative leaf areas were quantified between mock-inoculated and P. ultimum infected plants. Use of a glass-box container offered enhanced accessibility and minimized invasiveness for continuous and non-disruptive observation on the necrosis progression patterns along inoculated roots. With the assistance of a dissecting microscope, the genotype-specific resistance responses along the infected apple roots were captured and analyzed in detail. This reported phenotyping protocol represents a major development and should be easily adopted for other rosacea tree fruit crops with minor modifications.展开更多
The COVID-19 pandemic,which was caused by severe acute respiratory syndrome coronavirus 2(SARS-CoV-2),has become a worldwide health crisis due to its transmissibility.SARS-CoV-2 infection results in severe respiratory...The COVID-19 pandemic,which was caused by severe acute respiratory syndrome coronavirus 2(SARS-CoV-2),has become a worldwide health crisis due to its transmissibility.SARS-CoV-2 infection results in severe respiratory illness and can lead to significant complications in affected individuals.These complications encompass symptoms such as coughing,respiratory distress,fever,infectious shock,acute respiratory distress syndrome(ARDS),and even multiple-organ failure.Animal models serve as crucial tools for investigating pathogenic mechanisms,immune responses,immune escape mechanisms,antiviral drug development,and vaccines against SARS-CoV-2.Currently,various animal models for SARS-CoV-2 infection,such as nonhuman primates(NHPs),ferrets,hamsters,and many different mouse models,have been developed.Each model possesses distinctive features and applications.In this review,we elucidate the immune response elicited by SARS-CoV-2 infection in patients and provide an overview of the characteristics of various animal models mainly used for SARS-CoV-2 infection,as well as the corresponding immune responses and applications of these models.A comparative analysis of transcriptomic alterations in the lungs from different animal models revealed that the K18-hACE2 and mouse-adapted virus mouse models exhibited the highest similarity with the deceased COVID-19 patients.Finally,we highlighted the current gaps in related research between animal model studies and clinical investigations,underscoring lingering scientific questions that demand further clarification.展开更多
Severe acute respiratory syndrome coronavirus 2(SARS-CoV-2),the causative agent of COVID-19,encodes several accessory proteins that have been shown to play crucial roles in regulating the innate immune response.Howeve...Severe acute respiratory syndrome coronavirus 2(SARS-CoV-2),the causative agent of COVID-19,encodes several accessory proteins that have been shown to play crucial roles in regulating the innate immune response.However,their expressions in infected cells and immunogenicity in infected humans and mice are still not fully understood.This study utilized various techniques such as luciferase immunoprecipitation system(LIPS),immunofluorescence assay(IFA),and western blot(WB)to detect accessory protein-specific antibodies in sera of COVID-19 patients.Specific antibodies to proteins 3a,3b,7b,8 and 9c can be detected by LIPS,but only protein 3a antibody was detected by IFA or WB.Antibodies against proteins 3a and 7b were only detected in ICU patients,which may serve as a marker for predicting disease progression.Further,we investigated the expression of accessory proteins in SARS-CoV-2-infected cells and identified the expressions of proteins 3a,6,7a,8,and 9b.We also analyzed their ability to induce antibodies in immunized mice and found that only proteins 3a,6,7a,8,9b and 9c were able to induce measurable antibody productions,but these antibodies lacked neutralizing activities and did not protect mice from SARS-CoV-2 infection.Our findings validate the expression of SARS-CoV-2 accessory proteins and elucidate their humoral immune response,providing a basis for protein detection assays and their role in pathogenesis.展开更多
Disease progression prediction and therapeutic drug target discovery for Coronavirus disease 2019(COVID-19)are particularly important,as there is still no effective strategy for severe COVID-19 patient treatment.Herei...Disease progression prediction and therapeutic drug target discovery for Coronavirus disease 2019(COVID-19)are particularly important,as there is still no effective strategy for severe COVID-19 patient treatment.Herein,we performed multi-platform omics analysis of serial plasma and urine samples collected from patients during the course of COVID-19.Integrative analyses of these omics data revealed several potential therapeutic targets,such as ANXA1 and CLEC3B.Molecular changes in plasma indicated dysregulation of macrophage and suppression of T cell functions in severe patients compared to those in non-severe patients.Further,we chose 25 important molecular signatures as potential biomarkers for the prediction of disease severity.The prediction power was validated using corresponding urine samples and plasma samples from new COVID-19 patient cohort,with AUC reached to 0.904 and 0.988,respectively.In conclusion,our omics data proposed not only potential therapeutic targets,but also biomarkers for understanding the pathogenesis of severe COVID-19.展开更多
Persistent asymptomatic(PA)SARS-CoV-2 infections have been identified.The immune responses in these patients are unclear,and the development of effective treatments for these patients is needed.Here,we report a cohort...Persistent asymptomatic(PA)SARS-CoV-2 infections have been identified.The immune responses in these patients are unclear,and the development of effective treatments for these patients is needed.Here,we report a cohort of 23 PA cases carrying viral RNA for up to 191 days.PA cases displayed low levels of inflammatory and interferon response,weak antibody response,diminished circulating follicular helper T cells(cTfh),and inadequate specific CD4+and CD8+T-cell responses during infection,which is distinct from symptomatic infections and resembling impaired immune activation.Administration of a single dose of Ad5-nCoV vaccine to 10 of these PA cases elicited rapid and robust antibody responses as well as coordinated B-cell and cTfh responses,resulting in successful viral clearance.Vaccine-induced antibodies were able to neutralize various variants of concern and persisted for over 6 months,indicating long-term protection.Therefore,our study provides an insight into the immune status of PA infections and highlights vaccination as a potential treatment for prolonged SARS-CoV-2 infections.展开更多
Severe acute respiratory syndrome coronavirus 2(SARS-CoV-2),the causative agent of coronavirus disease 2019(COVID-19),has had a significant impact on healthcare systems and economies worldwide.The continuous emergence...Severe acute respiratory syndrome coronavirus 2(SARS-CoV-2),the causative agent of coronavirus disease 2019(COVID-19),has had a significant impact on healthcare systems and economies worldwide.The continuous emergence of new viral strains presents a major challenge in the development of effective antiviral agents.Strategies that possess broad-spectrum antiviral activities are desirable to control SARS-CoV-2 infection.ACE2,an angiotensin-containing enzyme that prevents the overactivation of the renin angiotensin system,is the receptor for SARS-CoV-2.ACE2 interacts with the spike protein and facilitates viral attachment and entry into host cells.Yet,SARS-CoV-2 infection also promotes ACE2 degradation.Whether restoring ACE2 surface expression has an impact on SARS-CoV-2 infection is yet to be determined.Here,we show that the ACE2-spike complex is endocytosed and degraded via autophagy in a manner that depends on clathrin-mediated endocytosis and PAK1-mediated cytoskeleton rearrangement.In contrast,free cellular spike protein is selectively cleaved into S1 and s2 subunits in a lysosomal-dependent manner.Importantly,we show that the pan-PAK inhibitor FRAX-486 restores ACE2 surface expression and suppresses infection by different SARS-CoV-2 strains.FRAX-486-treated Syrian hamsters exhibit significantly decreased lung viral load and alleviated pulmonary inflammation compared with untreated hamsters.In summary,our findings have identified novel pathways regulating viral entry,as well as therapeutic targets and candidate compounds for controlling the emerging strains of SARS-CoV-2 infection.展开更多
Dengue fever is a mosquito-borne viral disease spread in tropical and subtropical regions caused by the dengue virus(DENV).DENV causes a febrile illness,severe forms including hemorrhagic fevers and shock with fatalit...Dengue fever is a mosquito-borne viral disease spread in tropical and subtropical regions caused by the dengue virus(DENV).DENV causes a febrile illness,severe forms including hemorrhagic fevers and shock with fatalities in humans.DENV-2 is frequently associated with severe dengue infections and epidemics.DENV-2 strains from Guangdong,China,have not been characterized to compare the phylogenetics and pathogenicity of different DENV-2 subgenotype strains in both vitro and vivo.A total of 22 patients tested to be DENV-2 positive and were enrolled in this study,22 complete genomes were obtained by virus isolation and high-throughput sequencing.Phylogenetic and single amino polymorphism(SAP)analysis indicated that two major subgenotypes(A and C)of DENV-2 Cosmopolitan were prevalent in Guangdong in 2018.The apparent change of major subgenotypes of DENV-2 circulating in Guangdong indicated the diversity of DENV-2 strains,including endemic genotype and imported genotype.It alerted the risk of cross-border transmission of DENV.A significant difference in replication rate was observed in C6/36 between different DENV-2 strains,although growth kinetics comparison of different DENV-2 Cosmopolitan subgenotypes showed similar profiles.DENV-2 subgenotypes(A and C)replicated efficiently in IFNAR−/−C57BL/6 mice,and subgenotype A of Cosmopolitan infected mice showed increased weight loss and delayed viral clearance compared with the subgenotype C group.DENV-2 prevalent in Guangdong in 2018 showed apparent genetic and pathogenicity diversity in both vitro and vivo,indicating the necessity of molecular surveillance and exploration of the relationship between its pathogenicity and clinical characteristics.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
Dear Editor,The newly emerged severe acute respiratory syndrome coronavirus 2(SARS-CoV-2)Omicron subvariants(XBB.1,EG.5 and JN.1)and sublineages have been circulating globally with superior growth advantages over othe...Dear Editor,The newly emerged severe acute respiratory syndrome coronavirus 2(SARS-CoV-2)Omicron subvariants(XBB.1,EG.5 and JN.1)and sublineages have been circulating globally with superior growth advantages over other Omicron variants(Tamura et al.,2023).However,second-generation vaccines,including the BA.2 or BA.5 bivalent vaccine boosters,did not produce robust neutralization against the newly emerged XBB.1 or EG.5(Zou et al.,2023).Compared with variants BA.2 and BA.5,XBB.1 carries more mutations in the receptor binding domain(RBD)and exhibits significant immune evasion(Wang et al.,2023b).XBB.1 and its descendent lineages have rapidly become the dominant SARS-CoV-2 strain and are causing the next global wave of COVID-19.Therefore,it is essential to develop an updated vaccine against the newly emerged SARS-CoV-2 variants.展开更多
基金supported in part by the National Natural Science Foundation of China under Grants 32171909,51705365,52205254The Guangdong Basic and Applied Basic Research Foundation under Grants 2020B1515120050,2023A1515011255+2 种基金The Guangdong Key R&D projects under Grant 2020B0404030001the Scientific Research Projects of Universities in Guangdong Province under Grant 2020KCXTD015The Ji Hua Laboratory Open Project under Grant X220931UZ230.
文摘As computer technology continues to advance,factories have increasingly higher demands for detecting defects.However,detecting defects in a plant environment remains a challenging task due to the presence of complex backgrounds and defects of varying shapes and sizes.To address this issue,this paper proposes YOLO-DD,a defect detectionmodel based on YOLOv5 that is effective and robust.To improve the feature extraction process and better capture global information,the vanilla YOLOv5 is augmented with a new module called Relative-Distance-Aware Transformer(RDAT).Additionally,an Information Gap Filling Strategy(IGFS)is proposed to improve the fusion of features at different scales.The classic lightweight attention mechanism Squeeze-and-Excitation(SE)module is also incorporated into the neck section to enhance feature expression and improve the model’s performance.Experimental results on the NEU-DET dataset demonstrate that YOLO-DDachieves competitive results compared to state-of-the-art methods,with a 2.0% increase in accuracy compared to the original YOLOv5,achieving 82.41% accuracy and38.25FPS(framesper second).Themodel is also testedon a self-constructed fabric defect dataset,and the results show that YOLO-DD is more stable and has higher accuracy than the original YOLOv5,demonstrating its stability and generalization ability.The high efficiency of YOLO-DD enables it to meet the requirements of industrial high accuracy and real-time detection.
文摘In the post-genomics era, reliable phenotypes are considered the bottleneck for unraveling the genetic control over the biology of interest. Phenotyping resistance response of roots to infection by soilborne pathogen is more challenging compared to that of plant aerial parts. In additional to the hidden nature and small stature of fine roots where infection occurs, extra obstacles exist for rosaceae tree crops such as apple. Due to self-incompatible reproduction and high-level heterozygosity of apple genome, genetically identical apple plants cannot be produced through apple seed germination. Here we report an established phenotyping protocol which includes a streamlined tissue culture procedure for micropropagation of uniform apple plants, standardized inoculation procedure using Pythium ultimum, and multilayered evaluating methods on apple root resistance traits. Because of the implementation of tissue culture based micropropagation procedure, constant availability of the uniform plants with defined genetic background, equivalent age and non-contaminated roots overcame a longstanding barrier of systematic and detailed phenotypic characterization of apple root resistance traits. Repeated infection assays by root-dipping inoculation demonstrated the reproducible and wide-range plant survival rates, from single-digit to over 90% survived plants for a given genotype. Genotype-specific values due to P. ultimum inoculation on shoot and root biomass reduction, maximum root lengths, leaf number and cumulative leaf areas were quantified between mock-inoculated and P. ultimum infected plants. Use of a glass-box container offered enhanced accessibility and minimized invasiveness for continuous and non-disruptive observation on the necrosis progression patterns along inoculated roots. With the assistance of a dissecting microscope, the genotype-specific resistance responses along the infected apple roots were captured and analyzed in detail. This reported phenotyping protocol represents a major development and should be easily adopted for other rosacea tree fruit crops with minor modifications.
基金supported by a grant from the National Key R&D Program of China(No.2021YFC2301700 JS,2022YFC2604102 JS)Major Project of Guangzhou National Laboratory(GZNL2023A01003)+3 种基金the National Natural Science Foundation of China(82025001 JCZ,81971500 JXZ,2022YFC2303700 ARZ)the Guangdong Basic and Applied Basic Research Foundation(2022B1515020059 JS,2021B15150005 JXZ)the State Key Laboratory of Respiratory Disease(SKLRD-Z-202304,QTH)the ZHONGNANSHAN MEDICAIFOUNDATION OF GUANGDONG PROVINCE(No.ZNSA2020013 JCZ).
文摘The COVID-19 pandemic,which was caused by severe acute respiratory syndrome coronavirus 2(SARS-CoV-2),has become a worldwide health crisis due to its transmissibility.SARS-CoV-2 infection results in severe respiratory illness and can lead to significant complications in affected individuals.These complications encompass symptoms such as coughing,respiratory distress,fever,infectious shock,acute respiratory distress syndrome(ARDS),and even multiple-organ failure.Animal models serve as crucial tools for investigating pathogenic mechanisms,immune responses,immune escape mechanisms,antiviral drug development,and vaccines against SARS-CoV-2.Currently,various animal models for SARS-CoV-2 infection,such as nonhuman primates(NHPs),ferrets,hamsters,and many different mouse models,have been developed.Each model possesses distinctive features and applications.In this review,we elucidate the immune response elicited by SARS-CoV-2 infection in patients and provide an overview of the characteristics of various animal models mainly used for SARS-CoV-2 infection,as well as the corresponding immune responses and applications of these models.A comparative analysis of transcriptomic alterations in the lungs from different animal models revealed that the K18-hACE2 and mouse-adapted virus mouse models exhibited the highest similarity with the deceased COVID-19 patients.Finally,we highlighted the current gaps in related research between animal model studies and clinical investigations,underscoring lingering scientific questions that demand further clarification.
基金supported by grants from the National Natural Science Foundation of China(82002127,81971500,82025001,82172240)National Key R&D Program of China(2021YFC2301700,2022YFC2604100)+1 种基金Guangdong Basic and Applied Basic Research Foundation(2022B1515020059,2021B1515130005)R&D Program of Guangzhou Laboratory(EKPG21-30-2).
文摘Severe acute respiratory syndrome coronavirus 2(SARS-CoV-2),the causative agent of COVID-19,encodes several accessory proteins that have been shown to play crucial roles in regulating the innate immune response.However,their expressions in infected cells and immunogenicity in infected humans and mice are still not fully understood.This study utilized various techniques such as luciferase immunoprecipitation system(LIPS),immunofluorescence assay(IFA),and western blot(WB)to detect accessory protein-specific antibodies in sera of COVID-19 patients.Specific antibodies to proteins 3a,3b,7b,8 and 9c can be detected by LIPS,but only protein 3a antibody was detected by IFA or WB.Antibodies against proteins 3a and 7b were only detected in ICU patients,which may serve as a marker for predicting disease progression.Further,we investigated the expression of accessory proteins in SARS-CoV-2-infected cells and identified the expressions of proteins 3a,6,7a,8,and 9b.We also analyzed their ability to induce antibodies in immunized mice and found that only proteins 3a,6,7a,8,9b and 9c were able to induce measurable antibody productions,but these antibodies lacked neutralizing activities and did not protect mice from SARS-CoV-2 infection.Our findings validate the expression of SARS-CoV-2 accessory proteins and elucidate their humoral immune response,providing a basis for protein detection assays and their role in pathogenesis.
基金This work is supported by the grants from The National Key Research and Development Program of China(2018YFC1200100 to JC2L)National Science and Technology Major Project(2018ZX10301403 to JCZ.)+5 种基金the emergency grants for prevention and control of SARS-CoV-2 of Ministry of Science and Technology of Guangdong province(2020A111128008,2020B111112003,2018B020207013,2020B111108001 and 2020B1111320003 to JCZ,2020B1111330001 to NZ.)The National Program on Key Basic Research Project(2017YFC0906702 to Y.W.)National Key Technology R&D Program(2018YFC1311900 to N2.)Guangdong Science and Technology Foundation(2019B030316028,2020A1515010911 to NZ.)Guangzhou Medical University High-level University Innovation Team Training Program(Guangzhou Medical University released[2017]No.159 to JCZ and JX2.)111 project(D18010 to JCZI ).We thank the patients who took part in this study.
文摘Disease progression prediction and therapeutic drug target discovery for Coronavirus disease 2019(COVID-19)are particularly important,as there is still no effective strategy for severe COVID-19 patient treatment.Herein,we performed multi-platform omics analysis of serial plasma and urine samples collected from patients during the course of COVID-19.Integrative analyses of these omics data revealed several potential therapeutic targets,such as ANXA1 and CLEC3B.Molecular changes in plasma indicated dysregulation of macrophage and suppression of T cell functions in severe patients compared to those in non-severe patients.Further,we chose 25 important molecular signatures as potential biomarkers for the prediction of disease severity.The prediction power was validated using corresponding urine samples and plasma samples from new COVID-19 patient cohort,with AUC reached to 0.904 and 0.988,respectively.In conclusion,our omics data proposed not only potential therapeutic targets,but also biomarkers for understanding the pathogenesis of severe COVID-19.
基金the National Key R&D Program of China(2021YFC2302004 and 2021YFC2301102)National Natural Science Foundation of China(82172240,82101836,81901623 and 82201933)+6 种基金China National Postdoctoral Program for Innovative Talents(BX2021087),China Postdoctoral Science Foundation(2021M690787 and 2022M710892)Guangdong Basic and Applied Basic Research Foundation(2021B1515130005 and 2022B1515020059)Guangdong Medical Technology Research Foundation(B2022233)Guangzhou Science and Technology Planning Program Municipal School/Institute-Joint Funded Program(202102010143)PhD Startup Foundation from Guangzhou Women and Children’s Medical Center(2018-2020)State Key Laboratory of Respiratory Diseases Funded Program(SKLRD-Z-202330)Zhong Nanshan Medical Foundation of Guangdong Province(ZNSA-202001,ZNSXS-2020012,ZNSA-2020013 and ZNSXS-20220015).
文摘Persistent asymptomatic(PA)SARS-CoV-2 infections have been identified.The immune responses in these patients are unclear,and the development of effective treatments for these patients is needed.Here,we report a cohort of 23 PA cases carrying viral RNA for up to 191 days.PA cases displayed low levels of inflammatory and interferon response,weak antibody response,diminished circulating follicular helper T cells(cTfh),and inadequate specific CD4+and CD8+T-cell responses during infection,which is distinct from symptomatic infections and resembling impaired immune activation.Administration of a single dose of Ad5-nCoV vaccine to 10 of these PA cases elicited rapid and robust antibody responses as well as coordinated B-cell and cTfh responses,resulting in successful viral clearance.Vaccine-induced antibodies were able to neutralize various variants of concern and persisted for over 6 months,indicating long-term protection.Therefore,our study provides an insight into the immune status of PA infections and highlights vaccination as a potential treatment for prolonged SARS-CoV-2 infections.
基金the National Natural Science Foundation of China(NSFCNos.#82000007 toM.L.,#82001676 and#91842304 to B.T.L,#82125015 to Y.X.Z.#82272337 to J.F.W.C.)+7 种基金the GWCMC Postdoc Fund(Nos.#5001-3001061 to M.L.,#5001-3001060 to B.T.L.)Chongqing International Institute for Immunology(No.#2021YJC02 to Y.X.Z.)the Guangzhou Basic and Applied Basic Research Fund for Young Ph.D.scientists(No.#202102020194 to M.L.)Zhongnanshan Medical Foundation of Guangdong Province(No.#ZNSA-2020013 to J.C.Z.and Y.X.Z.)the General Research Fund(No.#17122322 to J.F.W.C.)Sanming Project of Medicine in Shenzhen,China(No.#SZSM201911014 to J.F.W.C.)the High Level-Hospital Program,Health Commission of Guangdong Province,China(to J.F.W.C.)and Emergency Collaborative Project(No.#EKPG22-01)of Guangzhou Laboratory(to J.F.W.C.).
文摘Severe acute respiratory syndrome coronavirus 2(SARS-CoV-2),the causative agent of coronavirus disease 2019(COVID-19),has had a significant impact on healthcare systems and economies worldwide.The continuous emergence of new viral strains presents a major challenge in the development of effective antiviral agents.Strategies that possess broad-spectrum antiviral activities are desirable to control SARS-CoV-2 infection.ACE2,an angiotensin-containing enzyme that prevents the overactivation of the renin angiotensin system,is the receptor for SARS-CoV-2.ACE2 interacts with the spike protein and facilitates viral attachment and entry into host cells.Yet,SARS-CoV-2 infection also promotes ACE2 degradation.Whether restoring ACE2 surface expression has an impact on SARS-CoV-2 infection is yet to be determined.Here,we show that the ACE2-spike complex is endocytosed and degraded via autophagy in a manner that depends on clathrin-mediated endocytosis and PAK1-mediated cytoskeleton rearrangement.In contrast,free cellular spike protein is selectively cleaved into S1 and s2 subunits in a lysosomal-dependent manner.Importantly,we show that the pan-PAK inhibitor FRAX-486 restores ACE2 surface expression and suppresses infection by different SARS-CoV-2 strains.FRAX-486-treated Syrian hamsters exhibit significantly decreased lung viral load and alleviated pulmonary inflammation compared with untreated hamsters.In summary,our findings have identified novel pathways regulating viral entry,as well as therapeutic targets and candidate compounds for controlling the emerging strains of SARS-CoV-2 infection.
基金funded by grants from the National Key Research and Development Program of China(2020YFC1200100,2018YFC1200100,2018ZX10301403)the Guangdong Provincial Department of Science and Technology(2020A1515010911,201803040006,2019B030316028)+2 种基金National Natural Science Foundation of China(81772191,91842106 and 8181101118,32000658)National Key Technology R&D Program(2018YFC1311900)Guangzhou Medical University High-level University Innovation Team Training Program(Guangzhou Medical University released[2017]No.159).
文摘Dengue fever is a mosquito-borne viral disease spread in tropical and subtropical regions caused by the dengue virus(DENV).DENV causes a febrile illness,severe forms including hemorrhagic fevers and shock with fatalities in humans.DENV-2 is frequently associated with severe dengue infections and epidemics.DENV-2 strains from Guangdong,China,have not been characterized to compare the phylogenetics and pathogenicity of different DENV-2 subgenotype strains in both vitro and vivo.A total of 22 patients tested to be DENV-2 positive and were enrolled in this study,22 complete genomes were obtained by virus isolation and high-throughput sequencing.Phylogenetic and single amino polymorphism(SAP)analysis indicated that two major subgenotypes(A and C)of DENV-2 Cosmopolitan were prevalent in Guangdong in 2018.The apparent change of major subgenotypes of DENV-2 circulating in Guangdong indicated the diversity of DENV-2 strains,including endemic genotype and imported genotype.It alerted the risk of cross-border transmission of DENV.A significant difference in replication rate was observed in C6/36 between different DENV-2 strains,although growth kinetics comparison of different DENV-2 Cosmopolitan subgenotypes showed similar profiles.DENV-2 subgenotypes(A and C)replicated efficiently in IFNAR−/−C57BL/6 mice,and subgenotype A of Cosmopolitan infected mice showed increased weight loss and delayed viral clearance compared with the subgenotype C group.DENV-2 prevalent in Guangdong in 2018 showed apparent genetic and pathogenicity diversity in both vitro and vivo,indicating the necessity of molecular surveillance and exploration of the relationship between its pathogenicity and clinical characteristics.
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 by a grant from the National Key R&D Program of China(2023YFC3041600 YW,the National Natural Science Foundation of China(82025001 JZ,92369113 YW,82172240 YW)Guangdong Basic and Applied Research Projects(2023B1515020040 YW,2021B1515130005 JZ,2021B1212030016 JD,2021A1111100009 JD)+7 种基金Science and Technology Planning Project of Guangzhou City(2023A04J1279 LZ)ZhongNanShan Medical Foundation of Guangdong Province(ZNSA-2020013 JZ)the Science and Technology Project of General Administration of Customs,P.R.China(2023HK065 LZ)State Key Laboratory of Respiratory Disease(SKLRD-Z-202214,SKLRD-OP-202309 YW,SKLRD-Z-202411 LZ)the Self-supporting Program of Guangzhou Laboratory(GZNL2023A01006,SRPG22-001)Guangzhou Medical University(YP2022005 YW)Korea Institute of Planning and Evaluation for Technology in Food,Agriculture and Forestry(IPET)through Animal Disease Management Technology Advancement Support Program,funded by the Ministry of Agriculture,Food and Rural Affairs(MAFRA)(122012-2,122060-2 JZ)the National Clinical Research Center for Respiratory Disease(BRD-NCRCRD,Guangzhou,Southern China).Patronus Biotech is a company researching virus-like particle display technology and vaccines.Yu Zhou and Jing Jin are named inventors on a patent invention relating to the described novel SARS-CoV-2 virus-like particle vaccine.All BALB/c mouse experiments complied with relevant ethical regulations for animal research and were approved by the LUYE PHARMA Animal Experimentation Ethics Committee.The K18-hACE2 mouse experiment was reviewed and approved by the Institutional Animal Care and Use Committees of Guangzhou Medical University(2023-0451).All authors declare that they have no conflict of interests.
文摘Dear Editor,The newly emerged severe acute respiratory syndrome coronavirus 2(SARS-CoV-2)Omicron subvariants(XBB.1,EG.5 and JN.1)and sublineages have been circulating globally with superior growth advantages over other Omicron variants(Tamura et al.,2023).However,second-generation vaccines,including the BA.2 or BA.5 bivalent vaccine boosters,did not produce robust neutralization against the newly emerged XBB.1 or EG.5(Zou et al.,2023).Compared with variants BA.2 and BA.5,XBB.1 carries more mutations in the receptor binding domain(RBD)and exhibits significant immune evasion(Wang et al.,2023b).XBB.1 and its descendent lineages have rapidly become the dominant SARS-CoV-2 strain and are causing the next global wave of COVID-19.Therefore,it is essential to develop an updated vaccine against the newly emerged SARS-CoV-2 variants.