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Endogenous retrovirus activation: potential for immunology and clinical applications

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National Science Review 2024年第4期11卷 21-23页

作者： Jundan Yu Peishan Qiu Jingwen Ai Bo Liu Guan-Zhu Han Fan Zhu Wenhong Zhang Jie Cui Department of Infectious Diseases Shanghai Key Laboratory of Infectious Diseases and Biosafety Emergency Response National Medical Center for Infectious Diseases Huashan Hospital Shanghai Medical College Fudan University CAS Key Laboratory of Molecular virology &Immunology Shanghai Institute of Immunity and Infection Chinese Academy of Sciences University of Chinese Academy of Sciences Shanghai Huashen institute of Microbes and Infections College of Life Sciences Nanjing Normal University State Key Laboratory of virology and Department of medical Microbiology School of Basic Medical SciencesWuhan University The institute of Infection and Health Research Fudan University Key Laboratory of medical Molecular virology(MOE/MOH) Shanghai Medical CollegeFudan University Laboratory for Marine Biology and Biotechnology Qingdao Marine Science and Technology Center

Endogenous retroviruses (ERVs), the remnants of ancient retrovirus infections, constitute approximately 8% of the human genome and play important roles in human evolution, development,and diseases. Multiple drugs, such as DNA methyltransferase inhibitors and lysine-specific histone demethylase 1inhibitors, reactivate ERVs, induce viral mimicry and trigger innate immune responses to enhance tumor immunogenicity.

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Mutations in the SARS-CoV-2 spike receptor binding domain and their delicate balance between ACE2 affinity and antibody evasion

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Protein & Cell 2024年第6期15卷 403-418页

作者： Song Xue Yuru Han Fan Wu Qiao Wang Key Laboratory of medical Molecular virology (MOE/NHC/CAMS) Shanghai Institute of Infectious Disease and BiosecurityShanghai Frontiers Science Center of Pathogenic Microorganisms and InfectionSchool of Basic Medical SciencesShanghai Medical CollegeFudan UniversityShanghai 200032China

Intensive selection pressure constrains the evolutionary trajectory of SARS-CoV-2 genomes and results in various novel variants with distinct mutation profiles.Point mutations,particularly those within the receptor binding domain(RBD)of SARS-CoV-2 spike(S)protein,lead to the functional alteration in both receptor engagement and monoclonal antibody(mAb)recognition.Here,we review the data of the RBD point mutations possessed by major SARS-CoV-2 variants and discuss their individual effects on ACE2 affinity and immune evasion.Many single amino acid substitutions within RBD epitopes crucial for the antibody evasion capacity may conversely weaken ACE2 binding affinity.However,this weakened effect could be largely compensated by specific epistatic mutations,such as N501Y,thus maintaining the overall ACE2 affinity for the spike protein of all major variants.The predominant direction of SARS-CoV-2 evolution lies neither in promoting ACE2 affinity nor evading mAb neutralization but in maintaining a delicate balance between these two dimensions.Together,this review interprets how RBD mutations efficiently resist antibody neutralization and meanwhile how the affinity between ACE2 and spike protein is maintained,emphasizing the significance of comprehensive assessment of spike mutations.

关键词： ACE2 affinity maintained

Resurgence of measles virus infection in an eliminated country, Sri Lanka

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Asian Pacific Journal of Tropical Medicine 2024年第5期17卷 208-213页

作者： Merennage Anusha Yasanthi Fernando Gankandage Prabhath Chathuranga Kaanthaka Gunaradha Abeygunasekara Dedunu Dias Weligamage Janaki Indira Abeynayake Department of medical Microbiology and Immunology Faculty of MedicineUniversity of ColomboSri Lanka Department of virology Medical Research InstituteColombo 08Sri Lanka Department of medical Administration Medical Research InstituteColombo 08Sri Lanka

Objective:To describe the situation of measles in Sri Lanka from May to November,2023 and to define the role of virology laboratory towards case confirmation and epidemiological and genetic characterization of the outbreak.Methods:This retrospective study analyzed all samples tested for measles from 1st of May to 30th of November,2023 at National Measles Rubella Laboratory,Sri Lanka.According to the World Health Organization(WHO)algorithm,serum and oropharyngeal/nasopharyngeal swabs were tested with WHO recommended kits for anti-measles IgM and measles virus specific RNA,respectively.Selected RNA positive samples were sequenced at reference laboratory,India.Analysis of sequencing data and construction of phylogenetic tree were carried out at National Measles Rubella Laboratory.Data was analyzed using descriptive statistics.Results:Of the total 1132 serum samples and 497 oropharyngeal/nasopharyngeal swabs from 1326 patients,657(49.5%)patients were confirmed as measles by anti-measles IgM,measles virus specific RNA or both.Males(55.6%,n=365)and the age group from>20 to≤30 years(33.0%,n=217)predominated positive patients.All provinces reported measles positive cases.All samples sequenced(100%,n=42)were genotype D8 with 95.2%(n=40)bearing Victoria.Australia origin.Conclusions:We described resurgence of measles in an eliminated country,confirming the genotype to be D8,one of the two genotypes currently circulating globally.Further,the study strongly convinced the importance of a strengthened virological surveillance system in an eliminated country,despite its eliminated status.

关键词： Measles elimination Resurgence of measles Sri Lanka Genotype D8 National Measles Rubella Laboratory

C1QTNF5 is a novel attachment factor that facilitates the entry of influenza A virus

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Virologica Sinica 2024年第2期39卷 277-289页

作者： Lei Yu Xinjin Liu Xiaoqin Wei Junrui Ren Xueyun Wang Shuwen Wu Ke Lan State Key Laboratory of virology Medical Research InstituteCollege of Life SciencesWuhan UniversityWuhan430072China Frontier Science Center for Immunology and Metabolism Wuhan UniversityWuhan430072China Taikang Center for Life and medical Sciences Wuhan UniversityWuhan430072China

Influenza A virus(IAV)binds sialic acid receptors on the cell surface to enter the host cells,which is the key step in initiating infection,transmission and pathogenesis.Understanding the factors that contribute to the highly efficient entry of IAV into human cells will help elucidate the mechanism of viral entry and pathogenicity,and provide new targets for intervention.In the present study,we reported a novel membrane protein,C1QTNF5,which binds to the hemagglutinin protein of IAV and promotes IAV infection in vitro and in vivo.We found that the HA1 region of IAV hemagglutinin is critical for the interaction with C1QTNF5 protein,and C1QTNF5 interacts with hemagglutinin mainly through its N-terminus(1–103 aa).In addition,we further demonstrated that overexpression of C1QTNF5 promotes IAV entry,while blocking the interaction between C1QTNF5 and IAV hemagglutinin greatly inhibits viral entry.However,C1QTNF5 does not function as a receptor to mediate IAV infection in sialic acid-deficient CHO-Lec2 cells,but promotes IAV to attach to these cells,suggesting that C1QTNF5 is an important attachment factor for IAV.This work reveals C1QTNF5 as a novel IAV attachment factor and provides a new perspective for antiviral strategies.

关键词： C1QTNF5 Influenza A virus Viral entry Hemagglutinin Attachment factor

Mutual antagonism of mouse-adaptation mutations in HA and PA proteins on H9N2 virus replication

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Virologica Sinica 2024年第1期39卷 56-70页

作者： Liping Ma Huabin Zheng Xianliang Ke Rui Gui Zhongzi Yao Jiasong Xiong Quanjiao Chen CAS Key Laboratory of Special Pathogens and Biosafety Wuhan Institute of VirologyChinese Academy of SciencesWuhan430207China Center for Biosafety Mega-Science Wuhan Institute of VirologyChinese Academy of SciencesWuhan430207China Hubei Jiangxia Laboratory Wuhan430207China University of Chinese Academy of Sciences Beijing100049China

Avian H9N2 viruses have wide host range among the influenza A viruses.However,knowledge of H9N2 mammalian adaptation is limited.To explore the molecular basis of the adaptation to mammals,we performed serial lung passaging of the H9N2 strain A/chicken/Hunan/8.27 YYGK3W3-OC/2018(3W3)in mice and identified six mutations in the hemagglutinin(HA)and polymerase acidic(PA)proteins.Mutations L226Q,T511I,and A528V of HA were responsible for enhanced pathogenicity and viral replication in mice;notably,HA-L226Q was the key determinant.Mutations T97I,I545V,and S594G of PA contributed to enhanced polymerase activity in mammalian cells and increased viral replication levels in vitro and in vivo.PA-T97I increased viral polymerase activity by accelerating the viral polymerase complex assembly.Our findings revealed that the viral replication was affected by the presence of PA-97I and/or PA-545V in combination with a triple-point HA mutation.Furthermore,the double-and triple-point PA mutations demonstrated antagonistic effect on viral replication when combined with HA-226Q.Notably,any combination of PA mutations,along with double-point HA mutations,resulted in antagonistic effect on viral replication.We also observed antagonism in viral replication between PA-545V and PA-97I,as well as between HA-528V and PA-545V.Our findings demonstrated that several antagonistic mutations in HA and PA proteins affect viral replication,which may contribute to the H9N2 virus adaptation to mice and mammalian cells.These findings can potentially contribute to the monitoring of H9N2 field strains for assessing their potential risk in mammals.

关键词： Influenza Avirus(IAV) H9N2 HA PA Antagonism Mouse adaptation

The value of toxicological analysis in acute poisoning patients with uncertain exposure histories:a retrospective and descriptive study from an institute of poisoning

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World Journal of Emergency Medicine 2024年第2期15卷 98-104页

作者： Qifang Shi Gen Ba Zhenyu Xia Zhengsheng Mao Hao Sun Jinsong Zhang institute of Poisoning Nanjing Medical UniversityNanjing 211100China Department of Emergency Medicine the First Affiliated Hospital of Nanjing Medical UniversityNanjing 210029China Department of Forensic Medicine Nanjing Medical UniversityNanjing 211166China The Key Laboratory of Modern Toxicology of Ministry of Education Nanjing Medical UniversityNanjing 211166China

BACKGROUND:In clinical practice,some patients might not be able or unwilling to provide a thorough history of medication and poison exposure.The aim of this study was to use toxicological analysis to examine the clinical characteristics of patients with acute poisoning whose exposure history was uncertain from a toxicological analysis perspective.METHODS:This was a retrospective and descriptive study from an institute of poisoning.Patient registration information and test reports spanning the period from April 1,2020 to March 31,2022,were obtained.Patients with uncertain exposure histories and who underwent toxicological analysis were included.Clinical manifestations and categories of toxics were analyzed.RESULTS:Among the 195 patients with positive toxicological analysis results,the main causes of uncertain exposure history was disturbance of consciousness(62.6%),unawareness(23.6%)and unwillingness or lack of cooperation(13.8%).The predominant clinical manifestations were disturbed consciousness(62.6%),followed by vomiting and nausea(14.4%)and liver function abnormalities(8.7%).A comparison of clinical manifestations between patients with positive and negative(n=99)toxicological analyses results revealed significantly different proportions of disturbances in consciousness(63%vs.21%),dizziness(1.5%vs.5.1%),multi-organ failure(1.5%vs.7.1%),and local pain(0 vs 4%).The main categories of substances involved were psychiatric medications(23.1%),sedatives(20.5%),insecticides(13.8%),and herbicides(12.8%).CONCLUSION:The clinical manifestations of acute poisoning in patients with an uncertain exposure history are diverse and nonspecific,and toxicological analysis plays a pivotal role in the diagnosis and differential diagnosis of such patients.

关键词： Acute poisoning Toxic exposure Toxicological analysis Clinical manifestation

Nasal vaccination of triple-RBD scaffold protein with flagellin elicits long-term protection against SARS-CoV-2 variants including JN.1

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Signal Transduction and Targeted Therapy 2024年第5期9卷 2312-2323页

作者： Xian Li Mengxin Xu Jingyi Yang Li Zhou Lin Liu Min Li Shasha Wang Mei-Qin Liu Zhixiang Huang Zhen Zhang Shuning Liu Yunqi Hu Haofeng Lin Bowen Liu Ying Sun Qingguo Wu Zheng-Li Shi Ke Lan Yu Chen Huimin Yan Yao-Qing Chen Wuhan institute of virology Chinese Academy of SciencesWuhanChina Vaccine and Immunology Research Center Translational Medical Research InstituteShanghai Public Health Clinical CenterFudan UniversityShanghaiChina University of Chinese Academy of Sciences BeijingChina School of Public Health(Shenzhen) Shenzhen Campus of Sun Yat-sen UniversityShenzhenGuangdongChina State Key Laboratory of virology Modern Virology Research CenterCollege of Life SciencesWuhan UniversityWuhanChina Aerosol Bio-Tech(Suzhou)Co. LTDSuzhouJiangsuChina National medical Products Administration Key Laboratory for Quality Monitoring and Evaluation of Vaccines and Biological Products Sun Yat-sen UniversityGuanzhouChina

Developing a mucosal vaccine against SARS-CoV-2 is critical for combatting the epidemic.Here,we investigated long-term immune responses and protection against SARS-CoV-2 for the intranasal vaccination of a triple receptor-binding domain(RBD)scaffold protein(3R-NC)adjuvanted with a flagellin protein(KFD)(3R-NC+KFDi.n).In mice,the vaccination elicited RBD-specific broad-neutralizing antibody responses in both serum and mucosal sites sustained at high level over a year.This long-lasting humoral immunity was correlated with the presence of long-lived RBD-specific IgG-and IgA-producing plasma cells,alongside the Th17 and Tfh17-biased T-cell responses driven by the KFD adjuvant.Based upon these preclinical findings,an open labeled clinical trial was conducted in individuals who had been primed with the inactivated SARS-CoV-2(IAV)vaccine.With a favorable safety profile,the 3R-NC+KFDi.n boost elicited enduring broad-neutralizing IgG in plasma and IgA in salivary secretions.To meet the challenge of frequently emerged variants,we further designed an updated triple-RBD scaffold protein with mutated RBD combinations,which can induce adaptable antibody responses to neutralize the newly emerging variants,including JN.1.Our findings highlight the potential of the KFD-adjuvanted triple-RBD scaffold protein is a promising prototype for the development of a mucosal vaccine against SARS-CoV-2 infection.

关键词： vaccination vaccine sustained

Ancient dormant virus remnant ERVW-1 drives ferroptosis via degradation of GPX4 and SLC3A2 in schizophrenia

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Virologica Sinica 2024年第1期39卷 31-43页

作者： Dongyan Zhang Xiulin Wu Xing Xue Wenshi Li Ping Zhou Zhao Lv Kexin Zhao Fan Zhu State Key Laboratory of virology and Department of medical Microbiology School of Basic Medical SciencesWuhan UniversityWuhan430071China Hubei Province Key Laboratory of Allergy&Immunology Wuhan UniversityWuhan430071China

Human endogenous retroviruses(HERVs)are remnants of retroviral infections in human germline cells from millions of years ago.Among these,ERVW-1(also known as HERV-W-ENV,ERVWE1,or ENVW)encodes the envelope protein of the HERV-W family,which contributes to the pathophysiology of schizophrenia.Additionally,neuropathological studies have revealed cell death and disruption of iron homeostasis in the brains of individuals with schizophrenia.Here,our bioinformatics analysis showed that differentially expressed genes in the human prefrontal cortex RNA microarray dataset(GSE53987)were mainly related to ferroptosis and its associated pathways.Clinical data demonstrated significantly lower expression levels of ferroptosis-related genes,particularly Glutathione peroxidase 4(GPX4)and solute carrier family 3 member 2(SLC3A2),in schizophrenia patients compared to normal controls.Further in-depth analyses revealed a significant negative correlation between ERVW-1 expression and the levels of GPX4/SLC3A2 in schizophrenia.Studies indicated that ERVW-1 increased iron levels,malondialdehyde(MDA),and transferrin receptor protein 1(TFR1)expression while decreasing glutathione(GSH)levels and triggering the loss of mitochondrial membrane potential,suggesting that ERVW-1 can induce ferroptosis.Ongoing research has shown that ERVW-1 reduced the expression of GPX4 and SLC3A2 by inhibiting their promoter activities.Moreover,Ferrostatin-1(Fer-1),the ferroptosis inhibitor,reversed the iron accumulation and mitochondrial membrane potential loss,as well as restored the expressions of ferroptosis markers GSH,MDA,and TFR1 induced by ERVW-1.In conclusion,ERVW-1 could promote ferroptosis by downregulating the expression of GPX4 and SLC3A2,revealing a novel mechanism by which ERVW-1 contributes to neuronal cell death in schizophrenia.

关键词： ERVW-1 Glutathione peroxidase 4(GPX4) Solute carrier family 3 member 2(SLC3A2) Ferroptosis Schizophrenia

Viromes of Haemaphysalis longicornis reveal different viral abundance and diversity in free and engorged ticks

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Virologica Sinica 2024年第2期39卷 194-204页

作者： Jian Xiao Xuan Yao Xuhua Guan Jinfeng Xiong Yaohui Fang Jingyuan Zhang You Zhang Abulimiti Moming Zhengyuan Su Jiayin Jin Yingying Ge Jun Wang Zhaojun Fan Shuang Tang Shu Shen Fei Deng Key Laboratory of virology and Biosafety and National Virus Resource Center Wuhan Institute of VirologyChinese Academy of SciencesWuhan430071China Hubei Provincial Center for Disease Control and Prevention Wuhan430070China University of Chinese Academy of Sciences Beijing101408China Hubei Jiangxia Laboratory Wuhan430200China Xinjiang Key Laboratory of Vector-borne Infectious Diseases Urumqi830002China Current address:Department of medical Laboratory The Second Affiliated HospitalHainan Medical UniversityHaikou57000China

Haemaphysalis longicornis ticks,commonly found in East Asia,can transmit various pathogenic viruses,includingthe severe fever with thrombocytopenia syndrome virus(SFTSV)that has caused febrile diseases among humansin Hubei Province.However,understanding of the viromes of H.longicornis was limited,and the prevalence ofviruses among H.longicornis ticks in Hubei was not well clarified.This study investigates the viromes of bothengorged(fed)and free(unfed)H.longicornis ticks across three mountainous regions in Hubei Province from 2019to 2020.RNA-sequencing analysis identified viral sequences that were related to 39 reference viruses belonging tounclassified viruses and seven RNA viral families,namely Chuviridae,Nairoviridae,Orthomyxoviridae,Parvoviridae,Phenuiviridae,Rhabdoviridae,and Totiviridae.Viral abundance and diversity in these ticks were analysed,andphylogenetic characteristics of the Henan tick virus(HNTV),Dabieshan tick virus(DBSTV),Okutama tick virus(OKTV),and Jingmen tick virus(JMTV)were elucidated based on their full genomic sequences.Prevalenceanalysis demonstrated that DBSTV was the most common virus found in individual H.longicornis ticks(12.59%),followed by HNTV(0.35%),whereas JMTV and OKTV were not detected.These results improve our understanding of H.longicornis tick viromes in central China and highlight the role of tick feeding status and geographyin shaping the viral community.The findings of new viral strains and their potential impact on public health raisethe need to strengthen surveillance efforts for comprehensively assessing their spillover potentials.

关键词： Ticks Virome Haemaphysalis longicornis Phylogenetic analysis Viral abundance and diversity