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RNA viromes of Dermacentor nuttalli ticks reveal a novel uukuvirus in Qinghai Province,China

Virologica Sinica 2024年第4期39卷 537-545页

作者： Yaohui Fang Jun Wang Jianqing Sun Zhengyuan Su Shengyao Chen Jian Xiao Jun Ni Zhihong Hu Yubang He Shu Shen Fei Deng Key laboratory of Special Pathogens and Biosafety and National Virus Resource Center Wuhan Institute of VirologyChinese Academy of SciencesWuhan 430071China University of Chinese Academy of Sciences Beijing 101408China Qinghai Lake National Nature Reserve Administration Xining 810000China Hubei Jiangxia laboratory Wuhan 430200China Xinjiang Key laboratory of Vector-borne Infectious Diseases Urumqi830002China

Ticks are a major parasite on the Qınghai-Tibet Plateau,western China,and represent an economic burden to agriculture and animal *** research on tick-borne pathogens that threaten humans and animals,the viromes of dominant tick species in this area remain *** this study,we collected Dermacentor nuttalli ticks near Qınghai Lake and identified 13 viruses belonging to at least six families through metagenomic *** viruses were of high abundance in pools,including Xınjiang tick-associated virus 1(XJTAV1),and three novel viruses:Qınghai Lake virus 1,Qınghai Lake virus 2(QHLV1,and QHLV2,unclassified),and Qınghai Lake virus 3(QHLV3,genus Uukuvirus of family Phenuiviridae in order Bunyavirales),which lacks the M *** minimum infection rates of the four viruses in the tick groups were 8.2%,49.5%,6.2%,and 24.7%,respectively,suggesting the prevalence of these viruses in *** ticks.A putative M segment of QHLV3 was identified from the next-generation sequencing data and further characterized for its signal peptide cleavage site,N-glycosylation,and transmembrane ***,we probed the L,M,and S segments of other viruses from sequencing data of other tick pools by using the putative M segment sequence of *** revealing the viromes of *** ticks,this study enhances our understanding of tick-borne viral communities in highland *** putative M segment identified in a novel uukuvirus suggests that previously identified uukuviruses without M segments should have had the same genome organization as typical *** findings will facilitate virus discovery and our understanding of the phylogeny of tick-borne uukuviruses.

关键词： Dermacentor nuttalli Qınghai Province Virome Uukuvirus M segment

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Myotis bat STING attenuates aging-related inflammation in female mice

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Zoological Research 2024年第5期45卷 961-971页

作者： Xi Wang Jing-Kun Jia Qi Wang Jing-Wen Gong Ang Li Jia Su Peng Zhou Wuhan Institute of virology Chinese Academy of SciencesWuhanHubei 430071China Guangzhou National laboratory Guangzhou International Bio IslandGuangzhouGuangdong 510005China University of Chinese Academy of Sciences Beijing 100000China State Key laboratory of Respiratory Disease First Affiliated Hospital of Guangzhou Medical SchoolGuangzhouGuangdong 510005China

Bats,notable as the only flying mammals,serve as natural reservoir hosts for various highly pathogenic viruses in humans(e.g.,SARS-CoV and Ebola virus).Furthermore,bats exhibit an unparalleled longevity among mammals relative to their size,particularly the Myotis bats,which can live up to 40 ***,the mechanisms underlying these distinctive traits remain incompletely *** our prior research,we demonstrated that bats exhibit dampened STING-interferon activation,potentially conferring upon them the capacity to mitigate virus-or aging-induced *** substantiate this hypothesis,we established the first in vivo bat-mouse model for aging studies by integrating Myotis davidii bat STING(MdSTING)into the mouse *** monitored the genotypes of these mice and performed a longitudinal comparative transcriptomic analysis on MdSTING and wild-type mice over a 3-year aging *** transcriptomic analysis indicated a reduction in aging-related inflammation in female MdSTING mice,as evidenced by significantly lower levels of pro-inflammatory cytokines and chemokines,immunopathology,and neutrophil recruitment in aged female MdSTING mice compared to aged wild-type mice in *** results indicated that MdSTING knock-in attenuates the aging-related inflammatory response and may also improve the healthspan in mice in a sex-dependent *** the underlying mechanism awaits further study,this research has critical implications for bat longevity research,potentially contributing to our comprehension of healthy aging in humans.

关键词： Bat STING Longevity Aging-related inflammation Virus reservoir host

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Interconnection of cellular autophagy and endosomal vesicle trafficking and its role in hepatitis B virus replication and release

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Virologica Sinica 2024年第1期39卷 24-30页

作者： Jia Li Yong Lin Xueyu Wang Mengji Lu Institute for virology University Hospital EssenUniversity of Duisburg-EssenEssen45122Germany Key laboratory of Molecular Biology of Infectious Diseases(Chinese Ministry of Education) Chongqing Medical UniversityChongqing400016China The Key laboratory for Diagnosis and Treatment of Infectious Diseases The First Affiliated HospitalCollege of MedicineZhejiang UniversityHangzhou310000China

Hepatitis B virus(HBV)produces and releases various particle types,including complete virions,subviral particles with envelope proteins,and naked *** studies demonstrate that HBV exploits distinct intracellular membrane trafficking pathways,including the endosomal vesicle trafficking and autophagy pathway,to assemble and release viral and subviral ***,we summarize the findings about the distinct roles of autophagy and endosomal membrane trafficking and the interaction of both pathways in HBV replication,assembly,and release.

关键词： Amphisome Autophagy Endosomal vesicle Hepatitis B virus(HBV)

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Emergence of highly pathogenic avian influenza A(H5N8)clade 2.3.4.4b viruses in grebes in Inner Mongolia and Ningxia,China,in 2021

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Journal of Integrative Agriculture 2024年第1期23卷 348-353页

作者： Qiuzi Xu Xinru Lü Yi Li Hua Luo Zhen Zhang Xiang Li Rongxiu Qin Qing An Fengyi Qu Zhenliang Zhao Chengbo Zhang Weidong Wang Yuecheng Li Yajun Wang Xiangwei Zeng Zhijun Hou Jingqiang Ren Yulong Wang Yanbing Li Hongliang Chai College of Wildlife and Protected Area Northeast Forestry UniversityHarbin 150040China Harbin Veterinary Research Institute Chinese Academy of Agricultural SciencesHarbin 150040China Wenzhou Key laboratory for virology and Immunology Institute of VirologyWenzhou UniversityWenzhou 325000China Ordos Forestry and Grassland Administration Ordos 017000China Monitoring Center for Terrestrial Wildlife Epidemic Diseases Yinchuan 750000China

Highly pathogenic avian influenza(HPAI)subtype H5Nx viruses have spread globally and are a major concern for poultry,wild birds,mammals,and even humans(de Vries et al.2015;Zeng et al.2022).The hemagglutinin(HA)genes of H5 subtype viruses have evolved into multiple clades and some of these clades have been further divided into subclades(Cui et al.2022).Clade 2.***.4.4H5N8 HPAI viruses(HPAIVs)have caused several waves of disease outbreaks in wild birds and domestic poultry(Wang et al.2022).

关键词： poultry Ningxia influenza

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NSUN2 mediates distinct pathways to regulate enterovirus 71 replication

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Virologica Sinica 2024年第4期39卷 574-586页

作者： Lishi Liu Zhen Chen Kui Zhang Haojie Hao Li Ma Haizhou Liu Baocheng Yu Shuang Ding Xueyan Zhang Miao Zhu Xiang Guo Yi Liu Haibin Liu Fang Huang Ke Peng Wuxiang Guan Center for Emerging Infectious Diseases Wuhan Institute of VirologyCenter for Biosafety Mega-ScienceChinese Academy of SciencesWuhanHubei430071China University of Chinese Academy of Sciences Beijing100049China Hubei Jiangxia laboratory WuhanHubei430200China

Increasing evidences suggest that the methyltransferase NSUN2 catalyzes 5-methylcytosine(m5C)modifications on viral RNAs,which are essential for the replication of various *** the function of m5C deposition is well characterized,other potential roles of NSUN2 in regulating viral replication remain largely *** this study,the m5C modified residues catalyzed by NSUN2 on enterovirus 71(EV71)RNAs were ***2,along with m5C modifications,played multiple roles during the EV71 life *** m5C modified nucleotides increased the translational efficiency and stability of EV71 ***,NSUN2 was found to target the viral protein VP1 for binding and promote its stability by inhibiting the ***,both viral replication and pathogenicity in mice were largely attenuated when functional m5C residues were *** together,this study characterizes distinct pathways mediated by NSUN2 in regulating EV71 replication,and highlights the importance of its catalyzed m5C modifications on EV71 RNAs for the viral replication and pathogenicity.

关键词： NSUN2 5-methylcytosine Enterovirus 71 Ubiquitination Pathogenicity

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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 *** 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)***,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 *** single amino acid substitutions within RBD epitopes crucial for the antibody evasion capacity may conversely weaken ACE2 binding ***,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 *** 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 ***,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

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Structure-based design of pan-coronavirus inhibitors targeting host cathepsin L and calpain-1

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Signal Transduction and Targeted Therapy 2024年第4期9卷 1651-1664页

作者： Xiong Xie Qiaoshuai Lan Jinyi Zhao Sulin Zhang Lu Liu Yumin Zhang Wei Xu Maolin Shao Jingjing Peng Shuai Xia Yan Zhu Keke Zhang Xianglei Zhang Ruxue Zhang jian Li Wenhao Dai Zhen Ge Shulei Hu Changyue Yu Jiang Wang Dakota Ma Mingyue Zheng Haitao Yang Gengfu Xiao Zihe Rao Lu Lu Leike Zhang Fang Bai Yao Zhao Shibo Jiang Hong Liu Drug Discovery and Design Center State Key Laboratory of Drug ResearchCAS Key Laboratory of Receptor ResearchShanghai Institute of Materia MedicaChinese Academy of SciencesShanghai 201203China University of Chinese Academy of Sciences Beijing 100049China Key laboratory of Medical Molecular virology(MOE/NHC/CAMS) School of Basic Medical SciencesShanghai Institute of Infectious Disease and BiosecurityFudan UniversityShanghai 200032China Shanghai Institute for Advanced Immunochemical Studies and School of Life Science and Technology ShanghaiTech UniversityShanghai 201210China State Key laboratory of virology Wuhan Institute of VirologyCenter for Biosafety Mega-ScienceChinese Academy of SciencesWuhan 430071China School of Chinese Materia Medica Nanjing University of Chinese Medicine138 Xian Lin RoadJiangsu 210023 NanjingChina School of Pharmaceutical Science and Technology Hangzhou Institute for Advanced StudyUCASHangzhou 310024China National Clinical Research Center for Infectious Disease Shenzhen Third People's HospitalShenzhen 518112China

Respiratory disease caused by coronavirus infection remains a global health *** several SARS-CoV-2-specific vaccines and direct-acting antivirals are available,their effcacy on emerging coronaviruses in the future,including SARS-CoV-2 variants,might be ***-targeting antivirals provide preventive and therapeutic strategies to overcome resistance and manage future outbreak of emerging *** L(CTSL)and calpain-1(CAPN1)are host cysteine proteases which play crucial roles in coronaviral entrance into cells and infection-related immune ***,two peptidomimetic a-ketoamide compounds,14a and 14b,were identified as potent dual target inhibitors against CTSL and *** X-ray crystal structures of human CTSL and CAPN1 in complex with 14a and 14b revealed the covalent binding of a-ketoamide groups of 14a and 14b to C25 of CTSL and C115 of *** showed potent and broad-spectrum anticoronaviral activities in vitro,and it is worth noting that they exhibited low nanomolar potency against SARS-CoV-2 and its variants of concern(VOCs)with ECso values ranging from 0.80 to 161.7 nM in various *** mechanistic exploration indicated that they exhibited anticoronaviral activity through blocking viral ***,14a and 14b exhibited good oral pharmacokinetic properties in mice,rats and dogs,and favorable safety in *** addition,both 14a and 14b treatments demonstrated potent antiviral potency against SARS-CoV-2 XBB 1.16 variant infection in a K18-hACE2 transgenic mouse *** 14b also showed effective antiviral activity against HCoV-OC43 infection in a mouse model with a final survival rate of 60%.Further evaluation showed that 14a and 14b exhibited excellent antiinflammatory effects in Raw 264.7 mouse macrophages and in mice with acute *** together,these results suggested that 14a and 14b are promising drug candidates,providing novel insight into developing pan-coronavirus inhibitors with anti

关键词： calpain overcome entrance

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Design and optimization of piperidinesubstituted thiophene[3,2-d]pyrimidine-based HIV-1 NNRTIs with improved drug resistance and pharmacokinetic profiles

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Acta Pharmaceutica Sinica B 2024年第7期14卷 3110-3124页

作者： Yanying Sun Zhenzhen Zhou Zhongling Shi Fabao Zhao Minghui Xie Zongji Zhuo Erik De Clercq Christophe Pannecouqueb Dongwei Kang Peng Zhan Xinyong Liu Department of Medicinal Chemistry Key Laboratory of Chemical Biology(Ministry of Education)School of Pharmaceutical SciencesShandong UniversityJinan 250012China Rega Institute for Medical Research Laboratory of Virology and ChemotherapyK.U.LeuvenLeuven B-3000Belgium China-Belgium Collaborative Research Center for Innovative Antiviral Drugs of Shandong Province Jinan 250012China

HIV-1 reverse transcriptase(RT)has received great attention as an attractive therapeutic target for acquired immune deficiency syndrome(AIDS),but the inevitable drug resistance and side effects have always been major challenges faced by non-nucleoside reverse transcriptase inhibitors(NNRTIs).This work aimed to identify novel chemotypes of anti-HIV-1 agents with improved drugresistance profiles,reduced toxicity,and excellent druggability.A series of diarylpyrimidine(DAPY)derivatives were prepared via structural modifications of the leads K-5a2 and *** them,15a with dimethylphosphine oxide moiety showed the most prominent antiviral potency against all of the tested viral panel,being 1.6-fold(WT,EC_(50) Z 1.75 nmol/L),3.0-fold(L100I,EC_(50) Z 2.84 nmol/L),2.4-fold(K103N,EC_(50) Z 1.27 nmol/L),3.3-fold(Y181C,EC50 Z 5.38 nmol/L),2.9-fold(Y188L,EC_(50) Z 7.96 nmol/L),2.5-fold(E138K,EC_(50) Z 4.28 nmol/L),4.8-fold(F227L/V106A,EC_(50) Z 3.76 nmol/L)and 5.3-fold(RES056,EC_(50) Z 15.8 nmol/L)more effective than that of the marketed drug *** docking results illustrated the detailed interactions formed by compound 15a and WT,F227L/V106A,and RES056 ***,15a-HCl carried outstanding pharmacokinetic(t1/2 Z 1.32 h,F Z 40.8%)and safety profiles(LD_(50)>2000 mg/kg),which demonstrated that 15a HCl is a potential anti-HIV-1 drug candidate.

关键词： HIV-1 NNRTIs NNIBP Structural alert Anti-HIV-1 drug candidate

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Natural evidence of coronaviral 2′-O-methyltransferase activity affecting viral pathogenesis via improved substrate RNA binding

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Signal Transduction and Targeted Therapy 2024年第6期9卷 2819-2834页

作者： Jikai Deng Shimin Yang Yingjian Li Xue Tan Jiejie Liu Yanying Yu Qiang Ding Chengpeng Fan Hongyun Wang Xianyin Chen Qianyun Liu Xiao Guo Feiyu Gong Li Zhou Yu Chen State Key laboratory of virology RNA InstituteCollege of Life Sciences and Frontier Science Center for Immunology and MetabolismWuhan UniversityWuhanChina School of Medicine Tsinghua UniversityBeijingChina School of Basic Medical Sciences Wuhan UniversityWuhanChina Animal Bio-Safety Level Ⅲ laboratory/Institute for Vaccine Research Wuhan University School of MedicineWuhanChina

Previous studies through targeted mutagenesis of K-D-K-E motif have demonstrated that 2′-O-MTase activity is essential for efficient viral replication and immune ***,the K-D-K-E catalytic motif of 2′-O-MTase is highly conserved across numerous viruses,including flaviviruses,vaccinia viruses,coronaviruses,and extends even to ***,we observed a stronger 2′-O-MTase activity in SARS-CoV-2 compared to SARS-CoV,despite the presence of a consistently active catalytic *** further identified critical residues(Leu-36,Asn-138 and Ile-153)which served as determinants of discrepancy in 2′-O-MTase activity between SARS-CoV-2 and *** residues significantly enhanced the RNA binding affinity of 2′-O-MTase and boosted its versatility toward RNA *** interest,a triple substitution(Leu^(36)→Ile^(36),Asn^(138)→His^(138),Ile^(153)→Leu^(153),from SARS-CoV-2 to SARS-CoV)within nsp16 resulted in a proportional reduction in viral 2′-O-methylation and impaired viral ***,it led to a significant upregulation of type I interferon(IFN-I)and proinflammatory cytokines both in vitro and vivo,relying on the cooperative sensing of melanoma differentiation-associated protein 5(MDA5)and laboratory of genetics and physiology 2(LGP2).In conclusion,our findings demonstrated that alterations in residues other than K-D-K-E of 2′-O-MTase may affect viral replication and subsequently influence *** changes in nsp16 residues is crucial as it may aid in identifying and assessing future alteration in viral pathogenicity resulting from natural mutations occurring in nsp16.

关键词： pathogenesis impaired alterations

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m^(1)A inhibition fuels oncolytic virus-elicited antitumor immunity via downregulating MYC/PD-L1 signaling

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International Journal of Oral Science 2024年第3期16卷 486-498页

作者： Shujin Li Tian Feng Yuantong Liu Qichao Yang An Song Shuo Wang Jun Xie Junjie Zhang Bifeng Yuan Zhijun Sun State Key laboratory of Oral&Maxillofacial Reconstruction and Regeneration Key Laboratory of Oral Biomedicine Ministry of EducationHubei Key Laboratory of StomatologySchool&Hospital of StomatologyFrontier Science Center for Immunology and MetabolismTaikang Center for Life and Medical SciencesWuhan UniversityWuhanChina School of Public Health Wuhan UniversityWuhanChina State Key laboratory of virology Medical Research InstituteWuhan UniversityWuhanChina Department of Oral Maxillofacial-Head Neck Oncology School and Hospital of StomatologyWuhan UniversityWuhanChina

N^(1)-methyladenosine(m^(1)A)RNA methylation is critical for regulating mRNA translation;however,its role in the development,progression,and immunotherapy response of head and neck squamous cell carcinoma(HNSCC)remains largely *** Tgfbr1 and Pten conditional knockout(2cKO)mice,we found the neoplastic transformation of oral mucosa was accompanied by increased m^(1)A modification *** of m^(1)A-associated genes identified TRMT61A as a key m^(1)A writer linked to cancer progression and poor ***,TRMT61A-mediated tRNA-m^(1)A modification promotes MYC protein synthesis,upregulating programmed death-ligand 1(PD-L1)***,m^(1)A modification levels were also elevated in tumors treated with oncolytic herpes simplex virus(oHSV),contributing to reactive PD-L1 *** m^(1)A inhibition sustained oHSV-induced antitumor immunity and reduced tumor growth,representing a promising strategy to alleviate *** findings indicate that m^(1)A inhibition can prevent immune escape after oHSV therapy by reducing PD-L1 expression,providing a mutually reinforcing combination immunotherapy approach.

关键词： immunity sustained representing

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