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Precore mutation enhances viral replication to facilitate persistent infection especially in HBeAg-negative patients

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Virologica Sinica 2024年第2期39卷 319-330页

作者： Guixin Li Danli Yang Xin Liu Ting Zhang Hui Liu Jun Zou Zimeng Xu Xiangmei Chen Lizhong Dai Hongsong Chen Fengmin Lu Peking University People's Hospital Peking University Hepatology InstituteBeijing Key Laboratory of Hepatitis C and Immunotherapy for Liver DiseasesBeijing International Cooperation Base for Science and Technology on NAFLD DiagnosisBeijing100044China Department of Microbiology and Infectious disease center School of Basic Medical SciencesPeking UniversityBeijing100191China Baruch S.Blumberg Institute DoylestownPA18901USA Shenzhen Sanyuansheng biotechnology Co. LtdShenzhen518000China Precision Medicine center of Zhengzhou University Academy of Medical SciencesZhengzhou UniversityZhengzhou450001China Peking University-Sansure biotech Joint Laboratory of Molecular Medicine Sansure Biotech Co.LtdChangsha410205China

Naturally occurred precore(PC,G1896A)and/or basal core promoter(BCP,A1762T/G1764A)mutations are prevalent in chronic HBV-infected patients,especially those under HBeAg-negative ***,the replicative capacity of HBV with PC/BCP mutations remains ***,meta-analysis showed that,only under HBeAg-negative status,the serum HBV DNA load in patients with PC mutation was 7.41-fold higher than those without the *** PC mutation alone and BCPþPC mutations promoted HBV replication in cell and hydrodynamic injection mouse *** human hepatocyte chimeric mouse model,BCPþPC mutations led to elevated replicative capacity and intrahepatic core protein ***,preC RNA harboring PC mutation could serve as mRNA to express core and P proteins,and such pgRNA-like function favored the maintenance of cccDNA pool under HBeAg-negative ***,BCPþPC mutations induced more extensive and severe human hepatocyte damage as well as activated endoplasmic reticulum stress and TNF signaling pathway in livers of chimeric *** study indicates that HBeAg-negative patients should be monitored on HBV mutations regularly and are expected to receive early antiviral treatment to prevent disease progression.

关键词： Hepatitis B virus Precore mutation Basal core promoter mutations Endoplasmic reticulum stress

Immune profiles of a COVID-19 adolescent with mild symptoms and anti anti-viral antibody deficiency

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Fundamental Research 2021年第2期1卷 117-123页

作者： Yang-dian Lai Ying-ying Chen Ji-ping Sun Yun Ling Jie Xu Youqiong Ye Lei Shen Hong-zhou Lu Bing Su Ying Wang Shanghai Institute of Immunology Department of Immunology and Microbiologyand the Ministry of Education Key Laboratory of Cell Death and DifferentiationShanghai Jiao Tong University School of MedicineShanghai200025China Department of Infectious disease Shanghai Public Health Clinical CenterShanghai201052China Department of Infectious disease Shanghai Ninth People's Hospital Shanghai Jiao Tong University School of MedicineShanghai200011China Key Laboratory of emergency Prevention Diagnosis and treatment of Respiratory DiseaseShanghai200025China

*** acute respiratory syndrome coronavirus 2(SARS-CoV-2)infection has led to the outbreak of COVID-19 syndrome since December 2019,becoming prevalent worldwide afterward[1,2].Unlike severe acute respiratory syndrome(SARS)and Middle East respiratory syndrome(MERS),which cause severe symptoms and high mortality[1],the morbidity from COVID-19 is relatively low,especially in young people[3].In China,the mortality rate was 1023 of 44,672 confirmed cases by the end of Februaryl 1,2020[4].However,there were no cases of death among 416 patients aged 0-9 years,and only 1 in 549 patients aged 10-19 years[4].The exact reasons for this clinical phenomenon remain unclear.

关键词： mortality acute respiratory

Characteristics of SARS-CoV-2 Delta variant-infected individuals with intermittently positive retest viral RNA after discharge

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National Science Review 2022年第10期9卷 63-66页

作者： Lu Li Jingyan Tang Zhiwei Xie Qingxin Gan Guofang Tang Zhongwei Hu Huimin Zeng Jingrong Shi Jiaojiao Li Yan Li Changwen Ke Min Kang Dan Liang Huan Lu Yuwei Tong Xilong Deng Jinxin Liu Hongzhou Lu Fuxiang Wang Fengyu Hu Feng Li Nanshan Zhong Xiaoping Tang Guangzhou Eighth People's Hospital Guangzhou Medical University Guangdong Provincial center for disease Control and Prevention The Third People's Hospital of Shenzhen Guangzhou Laboratory National Clinical Research center for Respiratory diseases of First Affiliated Hospital Guangzhou Medical University

SARS-CoV-2-infected patients will be discharged when viral ribonucleic acid(RNA) is consecutively negative at least twice over a 24-h ***,we have demonstrated that positive retest viral RNA,a particular clinical phenomenon initially observed in discharged SARS-CoV-2-infected patients in early 2020 [1,2],is the occasional reoccurrence of Polymerase Chain Reaction (PCR)-detectable viral RNA but not reinfection [3].Unfortunately,workable strategies to effectively discriminate against individuals likely to have positive retest viral RNA are still ***,for safety concerns,a mandatory minimum of 14-day quarantine in hospitals or hotels had been strictly applied for discharged *** that the Delta Variant of Concern (VOC),the dominant SARS-CoV-2 strain in 2021,

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Structural biology of SARS-CoV-2:open the door for novel therapies

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Signal Transduction and Targeted Therapy 2022年第2期7卷 423-450页

作者： Weizhu Yan Yanhui Zheng Xiaotao Zeng Bin He Wei Cheng Division of Respiratory and Critical Care Medicine Respiratory Infection and Intervention Laboratory of Frontiers Science Center for Disease-Related Molecular NetworkState Key Laboratory of BiotherapyWest China Hospital of Sichuan University610041 ChengduChina Department of emergency Medicine West China Hospital of Sichuan University610041 ChengduChina The First People’s Hospital of Longquanyi District Chengdu 610100 ChengduChina

Severe Acute Respiratory Syndrome Coronavirus-2(SARS-CoV-2)is the causative agent of the pandemic disease COVID-19,which is so far without efficacious *** discovery of therapy reagents for treating COVID-19 are urgently needed,and the structures of the potential drug-target proteins in the viral life cycle are particularly ***-CoV-2,a member of the Orthocoronavirinae subfamily containing the largest RNA genome,encodes 29 proteins including nonstructural,structural and accessory proteins which are involved in viral adsorption,entry and uncoating,nucleic acid replication and transcription,assembly and release,*** proteins individually act as a partner of the replication machinery or involved in forming the complexes with host cellular factors to participate in the essential physiological *** review summarizes the representative structures and typically potential therapy agents that target SARS-CoV-2 or some critical proteins for viral pathogenesis,providing insights into the mechanisms underlying viral infection,prevention of infection,and ***,these studies open the door for COVID therapies,leading to ways to prevent and treat COVID-19,especially,treatment of the disease caused by the viral variants are imperative.

关键词： prevention Acute typically

Human genetic basis of coronavirus disease 2019

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Signal Transduction and Targeted Therapy 2021年第10期6卷 2981-2994页

作者： Hao Deng Xue Yan Lamei Yuan Health Management center the Third Xiangya HospitalCentral South UniversityChangshaChina center for Experimental Medicine the Third Xiangya HospitalCentral South UniversityChangshaChina disease Genome Research center Central South UniversityChangshaChina Department of Neurology the Third Xiangya HospitalCentral South UniversityChangshaChina

Coronavirus disease 2019(COVID-19)caused by a novel coronavirus,severe acute respiratory syndrome coronavirus 2(SARS-CoV-2),has resulted in considerable morbidity and mortality ***-19 incidence,severity,and mortality rates differ greatly between populations,genders,ABO blood groups,human leukocyte antigen(HLA)genotypes,ethnic groups,and geographic *** highly heterogeneous SARS-CoV-2 infection is *** genetic factors such as variants in the angiotensin-converting enzyme gene(ACE),the angiotensin-converting enzyme 2 gene(ACE2),the transmembrane protease serine 2 gene(TMPRSS2),along with HLA genotype,and ABO blood group help to explain individual susceptibility,severity,and outcomes of *** review is focused on COVID-19 clinical and viral characteristics,pathogenesis,and genetic findings,with particular attention on genetic diversity and *** human genetic basis could provide scientific bases for disease prediction and targeted therapy to address the COVID-19 scourge.

关键词： mortality ABO acute

Transmission Dynamics and Epidemiological Characteristics of the SARS-CoV-2 Delta Variant ― Hunan Province, China, 2021

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China CDC weekly 2023年第3期5卷 56-62,I0006-I0009页

作者： Kaiwei Luo Yanpeng Wu Yan Wang Ziyan Liu Lan Yi Shanlu Zhao Xuemei Yan Hao Yang Kaiyuan Sun Marco Ajelli Shixiong Hu Hongjie Yu Hunan Provincial center for disease Control and Prevention Workstation for Emerging Infectious Disease Control and PreventionChinese Academy of Medical SciencesChangsha CityHunan ProvinceChina Shanghai Institute of Infectious disease and Biosecurity Fudan UniversityShanghai MunicipalityChina School of Public Health Fudan UniversityKey Laboratory of Public Health SafetyMinistry of EducationShanghai MunicipalityChina Division of International Epidemiology and Population Studies Fogarty International CenterNational Institutes of HealthBethesdaMDUSA Laboratory of Computational Epidemiology and Public Health Department of Epidemiology and BiostatisticsIndiana University School of Public HealthBloomingtonINUSA

Monitoring changes in the epidemiologic features between different severe acute respiratory syndrome coronavirus 2(SARS-CoV-2)variants is key to understanding the evolution of viral fitness in the host ***,we analyzed a successfully contained local outbreak of the Delta variant that took place in Hunan,China,in July–August,*** data on SARS-CoV-2 infections and their contacts were collected during the *** leveraging these data,we estimated key epidemiological parameters,including the incubation period,serial interval,and generation *** constructed a generalized linear mixed-effects model(GLMM)to quantify risk factors for Delta infection and *** July 28 and August 15,2021,a total of 129 infections and their 2,118 close contacts were identified during the outbreak in Hunan Province.

关键词： Hunan population Province

miR-204 suppresses porcine reproductive and respiratory syndrome virus(PRRSV)replication via inhibiting LC3B-mediated autophagy

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Virologica Sinica 2023年第5期38卷 690-698页

作者： Yao Yao Sihan Li Yingqi Zhu Yangyang Xu Siyuan Hao Shuyuan Guo Wen-Hai Feng State Key Laboratory of Animal biotech Breeding Frontiers Science Center for Molecular Design BreedingMinistry of Agriculture Key Laboratory of Soil Microbiologyand Department of Microbiology and ImmunologyCollege of Biological SciencesChina Agricultural UniversityBeijing100193China

Porcine reproductive and respiratory syndrome(PRRS)caused by PRRS virus(PRRSV)has been regarded as a persistent challenge for the swine farms ***(miRNAs)play key roles in regulating almost every important biological process,including virus-host *** this study,we found that miR-204 was highly expressed in cells that were not permissive to PRRSV infection compared with cells susceptible to PRRSV ***,we demonstrated that overexpression of miR-204 significantly inhibited PRRSV replication in porcine alveolar macrophages(PAMs).Through bioinformatic analysis,we found that there existed a potential binding site of miR-204 on the 30UTR of microtubule associated protein 1 light chain 3B(MAP1LC3B,LC3B),a hallmark of *** experiments including luciferase reporter assay and UV cross-linking and immunoprecipitation(CLIP)assay,we demonstrated that miR-204 directly targeted LC3B,thereby downregulating ***,we investigated the interplay between autophagy and PRRSV replication in PAMs,confirming that PRRSV infection induces autophagy,which in turn facilitates viral ***,we verify that miR-204 suppresses PRRSV replication via inhibiting LC3B-mediated autophagy in *** findings will provide a novel potential approach for us to develop antiviral therapeutic agents and controlling measures for future PRRSV outbreaks.

关键词： Porcine reproductive and respiratory syndrome virus(PRRSV) miR-204 Autophagy LC3B

Avian influenza viruses suppress innate immunity by inducingtrans-transcriptional readthrough via SSU72

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Cellular & Molecular Immunology 2022年第6期19卷 702-714页

作者： Yan Zhao Fengming Huang Zhen Zou Yuhai Bi Yang Yang Cong Zhang Qiang Liu Daozhen Shang Yiwu Yan Xiangwu Ju Song Mei Peng Xie Xiao Li Mingyao Tian Shuguang Tan Huijun Lu Zongsheng Han Kangtai Liu Yuqing Zhang Junbo Liang Zhu Liang Qingchao Zhang Jiahui Chang William JLiu Cong Feng Tanshi Li Michael Q.Zhang Xiaoyue Wang George FGao Yingxia Liu Ningyi Jin Chengyu Jiang State Key Laboratory of Medical Molecular Biology Institute of Basic Medical SciencesChinese Academy of Medical SciencesDepartment of BiochemistryPeking Union Medical CollegeBeijing 100005China Shenzhen Key Laboratory of Pathogen and Immunity State Key Discipline of Infectious DiseaseSecond Hospital Affiliated with Southern University of Science and TechnologyShenzhen Third People’s HospitalShenzhenGuangdong 518112China CAS Key Laboratory of Pathogenic Microbiology and Immunology Institute of MicrobiologyCenter for Influenza Research and Early-warning(CASCIRE)CAS-TWAS Center of Excellence for Emerging Infectious Diseases(CEEID)Chinese Academy of SciencesBeijing 100101China School of Life Science University of Science and Technology of ChinaHefeiAnhui 230027China Department of Automation Tsinghua UniversityBeijing 100084China Genetic Engineering Laboratory Institute of Military VeterinaryAcademy of Military Medical SciencesChangchunJilin 130062China State Key Laboratory of Biotherapy/Collaborative Innovation center for Biotherapy West China HospitalSichuan UniversityChengduSichuan 610000China State Key Laboratory of Medical Molecular Biology Department of Biochemistry and Center for BioinformaticsInstitute of Basic Medical SciencesChinese Academy of Medical SciencesSchool of Basic MedicinePeking Union Medical CollegeBeijing 100005China National Institute for viral disease Control and Prevention Chinese Centers for Disease Control and PreventionBeijing 102206China Department of emergency General Hospital of the PLAHaidian DistrictBeijing 100853China Department of Biological Sciences and center for Systems Biology The University of Texas at DallasRichardsonTXUSA

Innate immunity plays critical antiviral roles. The highly virulent avian influenza viruses (AIVs) H5N1, H7N9, and H5N6 can betterescape host innate immune responses than the less virulent seasonal H1N1 virus. Here, we report a mechanism by whichtranscriptional readthrough (TRT)-mediated suppression of innate immunity occurs post AIV infection. By using cell lines, mouselungs, and patient PBMCs, we showed that genes on the complementary strand (“trans” genes) influenced by TRT were involved inthe disruption of host antiviral responses during AIV infection. The trans-TRT enhanced viral lethality, and TRT abolishmentincreased cell viability and STAT1/2 expression. The viral NS1 protein directly bound to SSU72, and degradation of SSU72 inducedTRT. SSU72 overexpression reduced TRT and alleviated mouse lung injury. Our results suggest that AIVs infection induce TRT byreducing SSU72 expression, thereby impairing host immune responses, a molecular mechanism acting through the NS1-SSU72-trans-TRT-STAT1/2 axis. Thus, restoration of SSU72 expression might be a potential strategy for preventing AIV pandemics.

关键词： AIV infection TRT SSU72 NS1 Immune escape

Clinical characteristics of pediatric cases infected with the SARS-CoV-2 Omicron variant in a tertiary children's medical center in Shanghai,China

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World Journal of Pediatrics 2023年第1期19卷 87-95页

作者： Nan Shen Yu-Fen Wu Yi-Wei Chen Xiao-Yan Fang Min Zhou Wen-Yu Wang Ming-Yu Tang Qiu-Hui Pan Ji Ma Hao Zhang Qing Cao Department of Infectious disease Shanghai Children's Medical CenterNational Children's Medical CenterSchool of MedicineShanghai Jiao Tong UniversityDongfang Rd.1678Shanghai 200127China Department of Outpatient and emergency Shanghai Children's Medical CenterNational Children's Medical CenterSchool of MedicineShanghai Jiao Tong UniversityShanghai 200127China Department of Cardiology Shanghai Children's Medical CenterNational Children's Medical CenterSchool of MedicineShanghai Jiao Tong UniversityShanghai 200127China Department of Psychosomatic Medicine and Psychotherapy Klinikum Rechts Der IsarTechnische Universitat Munchen81675 MunichGermany Medical Department Shanghai Children's Medical CenterNational Children's Medical CenterSchool of MedicineShanghai Jiao Tong UniversityShanghai 200127China Department of Gastroenterology Shanghai Children's Medical CenterNational Children's Medical CenterSchool of MedicineShanghai Jiao Tong UniversityShanghai 200127China Department of Respiratory Medicine Shanghai Children's Medical CenterNational Children's Medical CenterSchool of MedicineShanghai Jiao Tong UniversityShanghai 200127China Department of Laboratory Medicine Shanghai Children's Medical CenterNational Children's Medical CenterSchool of MedicineShanghai Jiao Tong UniversityShanghai 200127China Shanghai Key Laboratory of Clinical Molecular Diagnostics for Pediatrics Shanghai 200127China Heart center and Shanghai Institute of Pediatric Congenital Heart disease Shanghai Children's Medical CenterNational Children's Medical CenterSchool of MedicineShanghai Jiao Tong UniversityDongfang Rd.1678Shanghai 200127China

Background The number of pediatric cases of infection with the severe acute respiratory syndrome coronavirus 2(SARS-CoV-2)Omicron variant has ***,we describe the clinical characteristics of children in a tertiary children's medical center in *** A total of 676 pediatric coronavirus disease 2019(COVID-19)cases caused by the Omicron variant who were admitted to the Shanghai Children's Medical center from March 28 to April 30,2022 were enrolled in this single-center,prospective,observational real-world *** demographics and clinical characteristics,especially COVID-19 vaccine status,were *** Children of all ages appeared susceptible to the SARS-CoV-2 Omicron variant,with no significant difference between sexes.A high SARS-CoV-2 viral load upon admission was associated with leukocytopenia,neutropenia,and thrombocytopenia(P=0.003,P=0.021,and P=0.017,respectively)but not with physical symptoms or radiographic chest *** linear regression models indicated that comorbidities(P=0.001)were associated with a longer time until viral clearance,and increasing age(Pviral *** analysis revealed an independent effect of comorbidities(Pdiseases(P<0.001).Conclusion This study describes the clinical characteristics of children infected with the Omicron variant of SARS-CoV-2 and calls for additional studies to evaluate the effectiveness and safety of vaccination against COVID-19 in children.

关键词： COVID-19vaccine Omicron variant Pediatric COVID-19 SARS-CoV-2