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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 replication.Here,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 cells.One 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 challenge.To 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 airway.TAT2-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 lungs.This 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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Another avian influenza A subtype jumping into human:this time is H7N4

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Science Bulletin 2018年第16期63卷 1025-1026页

作者： kwok-yung yuen State Key Laboratory of Emerging Infectious Diseases Li Ka Shing Faculty of Medicine University of Hong Kong

Avian influenza viruses have been first known to jump the interspecies barrier and cause human infections since 1959[1].However,avian influenza was not considered a serious threat to public health until 1997,when the influenza A(H5N1)virus caused an outbreak in Hong Kong with 18 cases including six deaths[2].The A(H5N1)epidemic has never stopped despite poultry immu-

关键词：流行性感冒病毒种鸟子类型公共健康家禽免疫盒子流行病死亡

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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 signs.Bat intestinal organoids,a unique model of bat intestinal epithelium,allow direct comparison with human intestinal organoids.We sought to unravel the cellular mechanism(s)underlying bat tolerance of coronaviruses by comparing the innate immunity in bat and human organoids.We optimized the culture medium,which enabled a consecutive passage of bat intestinal organoids for over one year.Basal expression levels of IFNs and IFN-stimulated genes were higher in bat organoids than in their human counterparts.Notably,bat organoids mounted a more rapid,robust and prolonged antiviral defense than human organoids upon Poly(I:C)stimulation.TLR3 and RLR might be the conserved pathways mediating antiviral response in bat and human intestinal organoids.The 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 viruses.Importantly,TLR3/RLR inhibition in bat organoids significantly boosted viral growth in the early phase after SARS-CoV-2 or CoV-HKU4 infection.Collectively,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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Intranasal administration of a single dose of a candidate live attenuated vaccine derived from an NSP16-deficient SARS-CoV-2 strain confers sterilizing immunity in animals

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Cellular & Molecular Immunology 2022年第5期19卷 588-601页

作者： Zi-Wei Ye Chon Phin Ong Kaiming Tang Yilan Fan Cuiting Luo Runhong Zhou Peng Luo Yun Cheng Victor Sebastien Gray Pui Wang Hin Chu Jasper Fuk-Woo Chan Kelvin Kai-Wang To Honglin Chen Zhiwei Chen kwok-yung yuen Guang Sheng Ling Shuofeng Yuan Dong-Yan Jin Department of Microbiology Li Ka Shing Faculty of MedicineThe University of Hong Kong102 Pokfulam RoadPokfulamHong KongChina State Key Laboratory of Emerging Infectious Diseases The University of Hong Kong102 Pokfulam RoadPokfulamHong KongChina School of Biomedical Sciences Li Ka Shing Faculty of MedicineThe University of Hong Kong21 Sassoon RoadPokfulamHong KongChina

Live attenuated vaccines might elicit mucosal and sterilizing immunity against SARS-CoV-2 that the existing mRNA,adenoviral vector and inactivated vaccines fail to induce.Here,we describe a candidate live attenuated vaccine strain of SARS-CoV-2 in which the NSP16 gene,which encodes 2′-O-methyltransferase,is catalytically disrupted by a point mutation.This virus,designated d16,was severely attenuated in hamsters and transgenic mice,causing only asymptomatic and nonpathogenic infection.A single dose of d16 administered intranasally resulted in sterilizing immunity in both the upper and lower respiratory tracts of hamsters,thus preventing viral spread in a contact-based transmission model.It also robustly stimulated humoral and cell-mediated immune responses,thus conferring full protection against lethal challenge with SARS-CoV-2 in a transgenic mouse model.The neutralizing antibodies elicited by d16 effectively cross-reacted with several SARS-CoV-2 variants.Secretory immunoglobulin A was detected in the blood and nasal wash of vaccinated mice.Our work provides proof-of-principle evidence for harnessing NSP16-deficient SARS-CoV-2 for the development of live attenuated vaccines and paves the way for further preclinical studies of d16 as a prototypic vaccine strain,to which new features might be introduced to improve safety,transmissibility,immunogenicity and efficacy.

关键词： Live attenuated vaccine NSP16 2'-O-methyltransferase T-cell response Mucosal immunity Sterilizing immunity

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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 illness.Advances 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 pandemic.Information 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 response.The 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 papain-like protease for broad-spectrum coronavirus inhibition

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Protein & Cell 2022年第12期13卷 940-953页

作者： Shuofeng Yuan Xiaopan Gao Kaiming Tang Jian-Piao Cai Menglong Hu Peng Luo Lei Wen Zi-Wei Ye Cuiting Luo Jessica Oi-Ling Tsang Chris Chun-Yiu Chan Yaoqiang Huang Jianli Cao Ronghui Liang Zhenzhi Qin Bo Qin Feifei Yin Hin Chu Dong-Yan Jin Ren Sun Jasper Fuk-Woo Chan Sheng Cui kwok-yung yuen State Key Laboratory of Emerging Infectious Diseases Li Ka Shing Faculty of MedicineThe University of Hong KongPokfulamHong Kong SARChina Department of Microbiology Li Ka ShingFaculty of MedicineThe University of Hong KongPokfulamHong Kong SARChina NHC Key Laboratory of Systems Biology of Pathogens Institute of Pathogen BiologyChinese Academy of Medical Sciences and Peking Union Medical CollegeBeijing 100730China School of Biomedical Sciences Li Ka Shing Faculty of MedicineThe University of Hong KongPokfulamHong Kong SARChina Department of Molecular and Medical Pharmacology David Geffen School of MedicineUniversity of California Los AngelesLos AngelesCAUSA Key Laboratory of Tropical Translational Medicine of Ministry of Education Hainan Medical UniversityHaikou 571199China Academician Workstation of Hainan Province Hainan Medical UniversityHaikou 571199China Hainan Medical University-The University of Hong Kong Joint Laboratory of Tropical Infectious Diseases The University of Hong KongPokfulamHong Kong Special Administrative RegionChina Guangzhou Laboratory Guangzhou 510320China Department of Clinical Microbiology and Infection Control The University of Hong Kong-Shenzhen HospitalShenzhen 518053China

The emergence of SARS-CoV-2 variants of concern and repeated outbreaks of coronavirus epidemics in the past two decades emphasize the need for next-generation pan-coronaviral therapeutics.Drugging the multi-functional papain-like protease(PLpro)domain of the viral nsp3 holds promise.However,none of the known coronavirus PLpro inhibitors has been shown to be in vivo active.Herein,we screened a structurally diverse library of 50,080 compounds for potential coronavirus PLpro inhibitors and identified a noncovalent lead inhibitor F0213 that has broad-spectrum anti-coronaviral activity,including against the Sarbecoviruses(SARSCoV-1 and SARS-CoV-2),Merbecovirus(MERS-CoV),as well as the Alphacoronavirus(hCoV-229E and hCoVOC43).Importantly,F0213 confers protection in both SARS-CoV-2-infected hamsters and MERS-CoV-infected human DPP4-knockin mice.F0213 possesses a dual therapeutic functionality that suppresses coronavirus replication via blocking viral polyprotein cleavage,as well as promoting antiviral immunity by antagonizing the PLpro deubiquitinase activity.Despite the significant difference of substrate recognition,mode of inhibition studies suggest that F0213 is a competitive inhibitor against SARS2-PLpro via binding with the 157K amino acid residue,whereas an allosteric inhibitor of MERSPLpro interacting with its 271E position.Our proof-ofconcept findings demonstrated that PLpro is a valid target for the development of broad-spectrum anticoronavirus agents.The orally administered F0213 may serve as a promising lead compound for combating the ongoing COVID-19 pandemic and future coronavirus outbreaks.

关键词： protease inhibitor coronavirus Nsp3 antiviral

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A critical role of IL-17 in modulating the B-cell response during H5N1 influenza virus infection

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Cellular & Molecular Immunology 2011年第6期8卷 462-468页

作者： Xiaohui Wang Chris CS Chan Min Yang Jun Deng Vincent KM Poon Virtual HC Leung King-Hung Ko Jie Zhou kwok yung yuen Bo-Jian Zheng Liwei Lu Department of Pathology The University of Hong KongHong KongChina Department of Microbiology The University of Hong KongHong KongChina Center of Infection and Immunology The University of Hong KongHong KongChina

Interleukin-17(IL-17),a member of the IL-17 cytokine family,plays a crucial role in mediating the immune response against extracellular bacteria and fungi in the lung.Although there is increasing evidence that IL-17 is involved in protective immunity against H1 and H3 influenza virus infections,little is known about the role of IL-17 in the highly pathogenic H5N1 influenza virus infection.In this study,we show that H5N1-infected IL-17 knockout(KO)mice exhibit markedly increased weight loss,more pronounced lung immunopathology and significantly reduced survival rates as compared with infected wild-type controls.Moreover,the frequency of B cells in the lung were substantially decreased in IL-17 KO mice after virus infection,which correlated with reduced CXCR5 expression in B cells and decreased CXCL13 production in the lung tissue of IL-17 KO mice.Consistent with this observation,B cells from IL-17 KO mice exhibited a significant reduction in chemokine-mediated migration in culture.Taken together,these findings demonstrate a critical role for IL-17 in mediating the recruitment of B cells to the site of pulmonary influenza virus infection in mice.

关键词： B cell H5N1 influenza virus IL-17 lung infection

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A six-year descriptive epidemiological study of human coronavirus infections in hospitalized patients in Hong Kong

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Virologica Sinica 2016年第1期31卷 41-48页

作者： Cyril C.Y.Yip Carol S.F.Lam Hayes K.H.Luk Emily Y.M.Wong Rodney A.Lee Lok-Yee So kwok-Hung Chan Vincent C.C.Cheng kwok-yung yuen Patrick C.Y.Woo Susanna K.P.Lau Department of Microbiology The University of Hong Kong Department of Microbiology Pamela Youde Nethersole Eastern Hospital Department of Paediatrics and Adolescent Medicine Pamela Youde Nethersole Eastern Hospital Research Centre of Infection and Immunology The University of Hong Kong State Key Laboratory of Emerging Infectious Diseases The University of Hong Kong

We conducted a six-year epidemiological study on human coronaviruses(HCoVs) circulating in Hong Kong, using 8275 nasopharyngeal samples from patients with acute respiratory tract infections. HCoVs were detected in 77(0.93%) of the samples by a pan-HCoV RT-PCR assay. The most frequently detected HCoV species was HCoV-OC43(0.58%), followed by HCoV-229E(0.15%),HCoV-HKU1(0.13%) and HCoV-NL63(0.07%). HCoVs were detected throughout the study period(September 2008–August 2014), with the highest detection rate from September 2010 to August2011(22/1500, 1.47%). Different seasonal patterns of each HCoV species in Hong Kong were noted.HCoV-OC43 was predominant in the fall and winter, whereas HCoV-HKU1 showed peak activity in winter, with a few cases occurred in spring and summer. HCoV-229 E mainly occurred in winter and spring, while HCoV-NL63 was predominant in summer and autumn. HCoVs most commonly infect the elderly and young children, with median age of 79.5 years(range, 22 days to 95 years).Intriguingly, the detection rate of HCoV-OC43 in the age group of > 80 years(26/2380, 1.09%) was significantly higher than that in the age group of 0–10 years(12/2529, 0.47%)(P < 0.05). These data provides new insight into the epidemiology of coronaviruses.

关键词：病毒学临床医学药物学

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Cellular response to influenza virus infection: a potential role for autophagy in CXCL10 and interferon-alpha induction

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Cellular & Molecular Immunology 2010年第4期7卷 263-270页

作者： Anna Hing-Yee Law Davy Chun-Wai Lee kwok-yung yuen Malik Peiris Allan Sik-Yin Lau Cytokine Biology Group Department of Paediatrics and Adolescent MedicineLi Ka Shing Faculty of MedicineThe University of Hong KongHong KongChina Department of Microbiology Li Ka Shing Faculty of MedicineThe University of Hong KongHong KongChina

Historically,influenza pandemics have arisen from avian influenza viruses.Avian influenza viruses H5N1 and H9N2 are potential pandemic candidates.Infection of humans with the highly pathogenic avian influenza H5N1 virus is associated with a mortality in excess of 60%,which has been attributed to dysregulation of the cytokine system.Human macrophages and epithelial cells infected with some genotypes of H5N1 and H9N2 viruses express markedly elevated cytokine and chemokine levels when compared with seasonal influenza A subtype H1N1 virus.The mechanisms underlying this cytokine and chemokine hyperinduction are not fully elucidated.In the present study,we demonstrate that autophagy,a tightly regulated homeostatic process for self-digestion of unwanted cellular subcomponents,plays a role in cytokine induction.Autophagy is induced to a greater extent by H9N2/G1,in association with cytokine hyperinduction,compared with H1N1 and the novel pandemic swine-origin influenza A/H1N1 viruses.Using 3-methyladenine to inhibit autophagy and small interfering RNA to silence the autophagy gene,Atg5,we further show that autophagic responses play a role in influenza virus-induced CXCL10 and interferon-a expression in primary human blood macrophages.Our results provide new insights into the pathogenic mechanisms of avian influenza viruses.

关键词： autophagy CXCL10 influenza interferon

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Leptotrichia hongkongensis sp.nov.,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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