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Unsynchronized butyrophilin molecules dictate cancer cell evasion of Vγ9Vδ2 T-cell killing

Cellular & Molecular Immunology 2024年第4期21卷 362-373页

作者： Zeguang Wu Qiezhong Lamao Meichao Gu Xuanxuan Jin Ying Liu Feng Tian Ying yu Pengfei yuan Shuaixin Gao Thomas S.Fulford Adam P.Uldrich Catherine C.L Wong Wensheng Wei Biomedical Pioneering Innovation Center Peking-Tsinghua Center for Life SciencesPeking University Genome Editing Research CenterState Key Laboratory of Protein and Plant Gene ResearchSchool of Life SciencesPeking University100871BeijingChina EdiGene Inc. Life Science ParkChangping District102206BeijingChina Center for Precision Medicine Multi-Omics Research Peking University Health Science CenterPeking University100191BeijingChina Department of Microbiology and Immunology at the Peter Doherty Institute for infection and Immunity The University of MelbourneParkvilleVIC3010Australia Cancer Immunology Program Peter MacCallum Cancer CentreMelbourneVICAustralia State Key Laboratory for Complex Severe and Rare DiseasesClinical Research InstitutePeking Union Medical College HospitalChinese Academy of Medical Science&Peking Union Medical CollegePeking-Tsinghua Center for Life Sciences100871BeijingChina

Vγ9Vδ2 T cells are specialized effector cells that have gained prominence as immunotherapy agents due to their ability to target and kill cells with altered pyrophosphate *** our effort to understand how cancer cells evade the cell-killing activity of Vγ9Vδ2 T cells,we performed a comprehensive genome-scale CRISPR screening of cancer *** found that four molecules belonging to the butyrophilin(BTN)family,specifically BTN2A1,BTN3A1,BTN3A2,and BTN3A3,are critically important and play unique,nonoverlapping roles in facilitating the destruction of cancer cells by primary Vγ9Vδ2 T *** coordinated function of these BTN molecules was driven by synchronized gene expression,which was regulated by IFN-γsignaling and the RFX ***,an enzyme called QPCTL was shown to play a key role in modifying the N-terminal glutamine of these BTN proteins and was found to be a crucial factor in Vγ9Vδ2 T cell killing of cancer *** our research,we offer a detailed overview of the functional genomic mechanisms that underlie how cancer cells escape Vγ9Vδ2 T ***,our findings shed light on the importance of the harmonized expression and function of gene family members in modulating T-cell activity.

关键词： Butyrophilin Vγ9Vδ2 T-cell Cancer-specific immune evasion Glutaminyl-peptide cyclotransferase-like Pyrophosphate metabolite Immunotherapy

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Pathogenesis of pandemic H1N1 2009 influenza virusinfection and the implication on management

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Frontiers of Medicine 2010年第2期4卷 147-156页

作者： Kelvin Kai-Wang TO Iris Wai-Sum LI Ivan Fan-Ngai HUNG Vincent Chi-Chung CHENG Kwok-yung yuEN carol yu Center for infection Department of MicrobiologyThe University of Hong KongHong Kong SARChina

The pandemic H1N12009 inﬂuenza virus has caused theﬁrst inﬂuenza pandemic of the 21st century,leading to disproportionate fatalities in the low-risk population despite the generally mild nature of the *** in science and technology have allowed very detailed study on the pathogenesis of this novel virus,and many have already been published in less than a year after the start of the *** generated from cell lines,animal models,and clinical data analysis has provided us with greater understanding of the behavior of this virus and the associated host *** new knowledge will allow us to formulate scientiﬁcally sound and evidence-based management plans.

关键词： inﬂuenza A virus,H1N1 subtype pandemic pathogenesis virulence factors immunity management,antiviral

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Targeting PKM2 signaling cascade with salvianic acid A normalizes tumor blood vessels to facilitate chemotherapeutic drug delivery

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Acta Pharmaceutica Sinica B 2024年第5期14卷 2077-2096页

作者： Cheng Qian yueke Zhou Teng Zhang Guanglu Dong Mengyao Song yu Tang Zhonghong Wei Suyun yu Qiuhong Shen Wenxing Chen Jaesung P.Choi Juming Yan Chongjin Zhong Li Wan Jia Li Aiyun Wang Yin Lu Yang Zhao Jiangsu Key Laboratory for Pharmacology and Safety Evaluation of Chinese Materia Medica Nanjing University of Chinese MedicineNanjing 210023China School of Medicine&Holistic Integrative Medicine Nanjing University of Chinese MedicineNanjing 210023China centre for Inflammation Faculty of ScienceCentenary InstituteSchool of Life SciencesUniversity of Technology SydneySydney NSW 2050Australia Jiangsu Key Laboratory of Immunity and Metabolism Department of Pathogenic Biology and ImmunologyNational Experimental Demonstration Center for Basic Medicine EducationXuzhou Laboratory of Infection and ImmunityXuzhou Medical UniversityXuzhou 221004China Department of General Surgery Jiangsu Province Hospital of Chinese MedicineAffiliated Hospital of Nanjing University of Chinese MedicineNanjing 210029China Macquarie Medical School Faculty of MedicineHuman Health SciencesMacquarie UniversitySydney NSW 2109Australia

Aberrant tumor blood vessels are prone to propel the malignant progression of tumors,and targeting abnormal metabolism of tumor endothelial cells emerges as a promising option to achieve vascular normalization and antagonize tumor ***,we demonstrated that salvianic acid A(SAA)played a pivotal role in contributing to vascular normalization in the tumor-bearing mice,thereby improving delivery and effectiveness of the chemotherapeutic *** was capable of inhibiting glycolysis and strengthening endothelial junctions in the human umbilical vein endothelial cells(HUVECs)exposed to ***,SAA was inclined to directly bind to the glycolytic enzyme PKM2,leading to a dramatic decrease in endothelial *** importantly,SAA improved the endothelial integrity via activating theβ-Catenin/Claudin-5 signaling axis in a PKM2-dependent *** findings suggest that SAA may serve as a potent agent for inducing tumor vascular normalization.

关键词： Salvianic acid A Tumor vascular normalization PKM2 β-Catenin Claudin-5 Endothelial glycolysis Tight junctions Doxorubicin

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Leptotrichia hongkongensis ***.,a novel Leptotrichia species with the oral cavity as its natural reservoir

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Journal of Zhejiang University-Science B(Biomedicine & Biotechnology) 2010年第6期11卷 391-401页

作者： Patrick C. Y. WOO Samson S. Y. WONG Jade L. L. TENG Kit-Wah LEUNG Antonio H. Y. NGAN Dong-qing ZHAO Herman TSE Susanna K. P. LAU Kwok-yung yuEN State Key Laboratory of Emerging Infectious Diseases The University of Hong Kong Hong Kong China Research centre of infection and Immunology The University of Hong Kong Hong Kong China Department of Microbiology The University of Hong Kong Hong Kong China carol yu centre for infection The University of Hong Kong Hong Kong China

A straight, non-sporulating, Gram-variable bacillus (HKU24T) was recovered from the blood culture of a patient with metastatic breast carcinoma. After repeated subculturing in BACTEC Plus Anaerobic/F blood culture broth, HKU24T grew on brucella agar as non-hemolytic, pinpoint colonies after 96 h of incubation at 37 °C in an anaerobic environment and aerobic environment with 5% CO2. Growth was enhanced with a streak of Staphylococcus aureus. HKU24T was non-motile and catalase-negative, but positive for alkaline phosphatase, β-glucosidase, and α-glucosidase. It hydrolyzed phenylphosphonate and reduced resazurin. 16S rRNA, groEL, gyrB, recA, and rpoB sequencing showed that HKU24T occupies a distinct phylogenetic position among the Leptotrichia species, being most closely related to Leptotrichia trevisanii. Using HKU24T groEL, gyrB, recA, and rpoB gene-specific primers, fragments of these genes were amplified from one of 20 oral specimens. Based on phenotypic and genotypic characteristics, we propose a new species, Leptotrichia hongkongensis sp. nov., to describe this bacterium.

关键词：关键词 Leptotrichia hongkongensis 细菌血文化厌氧的细菌新奇种类

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Romance of the three domains:how cladistics transformed the classifi cation of cellular organisms

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Protein & Cell 2013年第9期4卷 664-676页

作者： Chi-Chun Ho Susanna K.P.Lau Patrick C.Y.Woo Department of Microbiology The University of Hong KongHong KongChina State Key Laboratory of Emerging Infectious Diseases The University of Hong KongHong KongChina Research centre of infection and Immunology The University of Hong KongHong KongChina carol yu centre of infection The University of Hong KongHong KongChina

Cladistics is a biological philosophy that uses genealogi-cal relationship among species and an inferred sequence of divergence as the basis of classifi *** review critically surveys the chronological development of bio-logical classification from Aristotle through our post-genomic era with a central focus on *** 1957,Julian Huxley coined cladogenesis to denote splitting from *** 1960,the English translation of Willi Hennig’s 1950 work,Systematic Phylogenetics,was published,which received strong opposition from phenet-icists,such as numerical taxonomists Peter Sneath and Robert Sokal,and evolutionary taxonomist,Ernst Mayr,and sparked acrimonious debates in *** 1977-1990,Carl Woese pioneered in using small subunit rRNA gene sequences to delimitate the three domains of cellu-lar life and established major prokaryotic *** has since dominated *** being compatible with modern microbiological observations,*** with unusual phenotypes,restricted expression of charac-teristics and occasionally being uncultivable,increasing recognition of pervasiveness and abundance of horizon-tal gene transfer has challenged relevance and validity of *** mosaic nature of eukaryotic and prokary-otic genomes was also gradually *** the mid-2000s,high-throughput and whole-genome sequencing became routine and complex geneologies of organisms have led to the proposal of a reticulated web of *** genomics only indirectly leads to understanding of func-tional adaptations to ecological niches,computational modeling of entire organisms is underway and the gap between genomics and phenetics may soon be *** are not expected to settle as taxonomic classifi cations shall remain subjective to serve the human scientist,not the classifi ed.

关键词： cladistics phenetics phylogeny classifi ca-tion evolution

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Peptidic defective interfering gene nanoparticles against Omicron,Delta SARS-CoV-2 variants and influenza A virus in vivo

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Signal Transduction and Targeted Therapy 2022年第9期7卷 3484-3493页

作者： Hanjun Zhao Chuyuan Zhang Hoiyan Lam Xinjie Meng Zheng Peng Man Lung Yeung Jasper Fuk-Woo Chan Kelvin Kai-Wang To Kwok-yung yuen State Key Laboratory of Emerging Infectious Diseases Li Ka Shing Faculty of MedicineThe University of Hong KongHong Kong Special Administrative RegionChina Department of Microbiology School of Clinical MedicineLi Ka Shing Faculty of MedicineThe University of Hong KongHong Kong Special Administrative RegionChina centre for Virology Vaccinology and TherapeuticsHong Kong Science and Technology ParkHong Kong Special Administrative RegionChina Department of Infectious Disease and Microbiology The University of Hong Kong-Shenzhen HospitalShenzhenGuangdong ProvinceChina carol yu centre for infection The University of Hong KongPokfulamHong Kong Special Administrative RegionChina Guangzhou Laboratory GuangzhouGuangdong ProvinceChina

Defective interfering genes(DIGs)are short viral genomes and interfere with wild-type viral ***,we demonstrate that the new designed SARS-CoV-2 DIG(CD3600)can significantly inhibit the replication of SARS-CoV-2 including Alpha,Delta,Kappa and Omicron variants in human HK-2 cells and influenza DIG(PAD4)can significantly inhibit influenza virus replication in human A549 *** dose of influenza DIGs prophylactically protects 90%mice from lethal challenge of A(H1N1)pdm09 virus and CD3600 inhibits SARS-CoV-2 replication in hamster lungs when DIGs are administrated to lungs one day before viral *** further investigate the gene delivery vector in the respiratory tract,a peptidic TAT2-P1&LAH4,which can package genes to form small spherical nanoparticles with high endosomal escape ability,is demonstrated to dramatically increase gene expression in the lung ***2-P1&LAH4,with the dual-functional TAT2-P1(gene-delivery and antiviral),can deliver CD3600 to significantly inhibit the replication of Delta and Omicron SARS-CoV-2 in hamster *** peptide-based nanoparticle system can effectively transfect genes in lungs and deliver DIGs to inhibit SARS-CoV-2 variants and influenza virus in vivo,which provides the new insight into the drug delivery system for gene therapy against respiratory viruses.

关键词： influenza vivo Delta

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P21-activated kinase 1 (PAK1)-mediated cytoskeleton rearrangement promotes SARS-CoV-2 entry and ACE2 autophagic degradation

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Signal Transduction and Targeted Therapy 2023年第11期8卷 5353-5367页

作者： Ming Liu Bingtai Lu yue Li Shuofeng yuan Zhen Zhuang Guangyu Li Dong Wang Liuheyi Ma Jianheng Zhu Jinglu Zhao Chris Chung-Sing Chan Vincent Kwok-Man Poon Kenn Ka-Heng Chik Zhiyao Zhao Huifang Xian Jingxian Zhao Jincun Zhao Jasper Fuk-Woo Chan yuxia Zhang Guangzhou Institute of Pediatrics Guangzhou Women and Children's Medical CentreState Key Laboratory of Respiratory DiseasesGuangzhou Medical University510623 GuangzhouGuangdongChina Medical Research Institute Guangdong Provincial People's Hospital(Guangdong Academy of Medical Sciences)Southern Medical UniversityGuangdongChina State Key Laboratory of Emerging Infectious Diseases Carol Yu Centre for InfectionDepartment of MicrobiologySchool of Clinical MedicineLi Ka Shing Faculty of MedineThe University of Hong KongPokfulamHong KongChina Department of Clinical Microbiology and infection Control The University of Hong Kong Shenzhen HospitalShenzhenGuangdongChina centre for Virology Vaccinology and TherapeuticsHong Kong Science and Technology ParkHong KongChina State Key Laboratory of Respiratory Disease National Clinical Research Center for Respiratory DiseaseGuangzhou Institute of Respiratory Healththe First Affliated Hospital of Guangzhou Medical UniversityGuangzhouChina The Third Afliated Hospital of Zhengzhou University 450052 ZhengzhouChina Guangzhou Laboratory GuangzhouGuangdong ProvinceChina Chongqing International Institute for Immunology ChongqingChina

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 *** continuous emergence of new viral strains presents a major challenge in the development of effective antiviral *** that possess broad-spectrum antiviral activities are desirable to control SARS-CoV-2 ***2,an angiotensin-containing enzyme that prevents the overactivation of the renin angiotensin system,is the receptor for ***2 interacts with the spike protein and facilitates viral attachment and entry into host ***,SARS-CoV-2 infection also promotes ACE2 *** restoring ACE2 surface expression has an impact on SARS-CoV-2 infection is yet to be ***,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 *** contrast,free cellular spike protein is selectively cleaved into S1 and s2 subunits in a lysosomal-dependent ***,we show that the pan-PAK inhibitor FRAX-486 restores ACE2 surface expression and suppresses infection by different SARS-CoV-2 ***-486-treated Syrian hamsters exhibit significantly decreased lung viral load and alleviated pulmonary inflammation compared with untreated *** 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.

关键词： ACE2 inflammation rearrangement

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Analogous comparison unravels heightened antiviral defense and boosted viral infection upon immunosuppression in bat organoids

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Signal Transduction and Targeted Therapy 2023年第1期8卷 276-287页

作者： Xiaojuan Liu Cun Li Zhixin Wan Man Chun Chiu Jingjing Huang Yifei yu Lin Zhu Jian-Piao Cai Lei Rong You-qiang Song Hin Chu Zongwei Cai Shibo Jiang Kwok-yung yuen Jie Zhou Department of Microbiology School of Clinical MedicineLi Ka Shing Faculty of MedicineThe University of Hong KongHong KongChina State Key Laboratory of Environmental and Biological Analysis Department of ChemistryHong Kong Baptist UniversityHong KongChina Department of Medicine The University of Hong KongShenzhen HospitalShenzhenGuangdongChina School of Biomedical Sciences State Key Laboratory of Brain and Cognitive SciencesThe University of HongkongHong KongChina State Key Laboratory of Emerging Infectious Diseases Carol Yu Centre for InfectionThe University of Hong KongHong KongChina centre for Virology Vaccinology and TherapeuticsHong Kong Science and Technology ParkHong KongChina Key Laboratory of Medical Molecular Virology(MOE/NHC/CAMS) Institute of Infectious Disease and BiosecuritySchool of Basic Medical SciencesFudan UniversityShanghaiChina

Horseshoe bats host numerous SARS-related coronaviruses without overt disease *** intestinal organoids,a unique model of bat intestinal epithelium,allow direct comparison with human intestinal *** sought to unravel the cellular mechanism(s)underlying bat tolerance of coronaviruses by comparing the innate immunity in bat and human *** optimized the culture medium,which enabled a consecutive passage of bat intestinal organoids for over one *** expression levels of IFNs and IFN-stimulated genes were higher in bat organoids than in their human ***,bat organoids mounted a more rapid,robust and prolonged antiviral defense than human organoids upon Poly(I:C)***3 and RLR might be the conserved pathways mediating antiviral response in bat and human intestinal *** susceptibility of bat organoids to a bat coronavirus CoV-HKU4,but resistance to EV-71,an enterovirus of exclusive human origin,indicated that bat organoids adequately recapitulated the authentic susceptibility of bats to certain ***,TLR3/RLR inhibition in bat organoids significantly boosted viral growth in the early phase after SARS-CoV-2 or CoV-HKU4 ***,the higher basal expression of antiviral genes,especially more rapid and robust induction of innate immune response,empowered bat cells to curtail virus propagation in the early phase of infection.

关键词： boost comparison mounted

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Two-dimensional gel electrophoresis in bacterial proteomics

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Protein & Cell 2012年第5期3卷 346-363页

作者： Shirly O.T.Curreem Rory M.Watt Susanna K.P.Lau Patrick C.Y.Woo Department of Microbiology The University of Hong KongQueen Mary HospitalHong KongChina Oral Biosciences Faculty of DentistryThe University of Hong KongQueen Mary HospitalHong KongChina State Key Laboratory of Emerging Infectious Diseases Department of MicrobiologyThe University of Hong KongQueen Mary HospitalHong KongChina Research centre of infection and Immunology The University of Hong KongQueen Mary HospitalHong KongChina carol yu centre of infection The University of Hong KongHong KongChina

Two-dimensional gel electrophoresis(2-DE)is a gel-based technique widely used for analyzing the pro-tein composition of biological *** is capable of resolving complex mixtures containing more than a thousand protein components into individual protein spots through the coupling of two orthogonal bio-physical separation techniques:isoelectric focusing(first dimension)and polyacrylamide gel electrophore-sis(second dimension).2-DE is ideally suited for ana-lyzing the entire expressed protein complement of a bacterial cell:its *** relative simplicity and good reproducibility have led to 2-DE being widely used for exploring proteomics within a wide range of envi-ronmental and medically-relevant *** we give a broad overview of the basic principles and his-torical development of gel-based proteomics,and how this powerful approach can be applied for studying bacterial biology and *** highlight specific 2-DE applications that can be used to analyze when,where and how much proteins are *** links between proteomics,genomics and mass spectrometry are *** explore how proteomics involving tandem mass spectrometry can be used to analyze(post-translational)protein modifications or to identify proteins of unknown origin by de novo peptide *** use of proteome fractionation tech-niques and non-gel-based proteomic approaches are also *** highlight how the analysis of pro-teins secreted by bacterial cells(secretomes or exo-proteomes)can be used to study infection processes or the immune *** review is aimed at non-specialists who wish to gain a concise,compre-hensive and contemporary overview of the nature and applications of bacterial proteomics.

关键词： two-dimensional gel electrophoresis bacte-ria proteomics

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Angiotensin-converting enzyme 2:virus accomplice or host defender?

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Journal of Bio-X Research 2023年第3期6卷 93-103页

作者： Jiyan Wang Hongkai Chang Yaya Qiao Huanran Sun Xichuan Li Shuofeng yuan Shuai Zhang Changliang Shan State Key Laboratory of Medicinal Chemical Biology College of Pharmacy and Tianjin Key Laboratory of Molecular Drug ResearchNankai UniversityTianjin 300350China Tianjin Key Laboratory of Animal and Plant Resistance College of Life SciencesTianjin Normal UniversityTianjin 300387China State Key Laboratory of Emerging Infectious Diseases Carol Yu Centre for InfectionDepartment of MicrobiologyLi Ka Shing Faculty of MedicineThe University of Hong KongPokfulam 999077Hong Kong Special Administrative RegionChina School of Integrative Medicine Tianjin University of Traditional Chinese MedicineTianjin 301617China

Objective:Coronavirus disease 2019(COVID-19)caused by severe acute respiratory syndrome coronavirus 2(SARS-CoV-2)has led to social disruptions,mainly because we know too little about *** and Results:In this study,we integrated RNA sequencing results and found that SARS-CoV-2 infection alters aerobic glycolysis,the oxidative pentose phosphate pathway(oxiPPP),and DNA replication in lung tissues and ***,the direction of metabolic flux and DNA replication are dominated by angiotensin-converting enzyme 2(ACE2),a host cell-expressed viral receptor *** interestingly,although hosts with a high expression of ACE2 are more likely to be infected with SARS-CoV-2,the invading virus cannot perform nucleic acid replication well due to the restriction of glucose metabolism,eventually resulting in a prolonged infection cycle or infection ***:Our findings preliminarily explain the reasons for the emergence of asymptomatic infections at an early stage,which will provide assistance for the development of detection methods for diagnosing COVID-19.

关键词： ACE2 asymptomatic infection COVID-19 metabolism SARS-CoV-2

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