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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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Enhanced replication of SARS-CoV-2 Omicron BA.2 in human forebrain and midbrain organoids

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Signal Transduction and Targeted Therapy 2022年第12期7卷 4257-4260页

作者： Yuxin Hou chang Li Chaemin Yoon On Wah Leung Sikun You Xiaoming Cui jasper fuk-woo chan Duanqing Pei Hoi Hung Cheung Hin Chu State Key Laboratory of Emerging Infectious Diseases Department of MicrobiologySchool of Clinical MedicineLi Ka Shing Faculty of MedicineThe University of Hong Kongand Centre for VirologyVaccinology and TherapeuticsHong Kong Science and Technology ParkHong Kong Special Administrative RegionChina State Key Laboratory of Emerging Infectious Diseases Department of MicrobiologySchool of Clinical MedicineLi Ka Shing Faculty of MedicineThe University of Hong Kong Centre for Virology Vaccinology and TherapeuticsHong Kong Science and Technology ParkHong Kong Special Administrative RegionChina

Dear Editor,Coronavirus Disease 2019(COVID-19)is associated with a variety of neurological complications,including encephalopathy,encephalitis,dementia,and others.1 The pathogenic mechanism of these neurological manifestations remains incompletely understood but may be due to factors such as coagulation problem,immune-mediated response,or direct viral invasion into the central nervous system(CNS).2 We and others previously reported that ancestral SARS-CoV-2 could infect and replicate in human brain organoids.3,4 More recently,SARS-CoV-2 Omicron BA.1 emerged in late 2021 and demonstrated altered virological features including increased immunoevasion and attenuated pathogenicity comparing to SARS-CoV-2 wildtype(WT)and previous variants.5 However,the neuroinvasiveness of Omicron sublineages remain ***,we investigated the neuroinvasion and neurotoxicity of Omicron BA.1 and BA.2,and compared the findings with those of SARS-CoV-2 WT and Delta in human forebrain and midbrain *** results demonstrated that BA.2 replicated more efficiently while triggered lower levels of type I interferon response than that of SARS-CoV-2 WT,Delta,and BA.1 in both human forebrain and midbrain *** addition,BA.2 triggered substantially higher levels of apoptosis in the infected human forebrain and midbrain ***,these findings suggest that BA.2 may be different from SARS-CoV-2 WT and previous variants in its capacity in targeting and causing diseases in the human brain.

关键词： invasion finding incomplete

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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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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 ***,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 *** 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 *** also robustly stimulated humoral and cell-mediated immune responses,thus conferring full protection against lethal challenge with SARS-CoV-2 in a transgenic mouse *** neutralizing antibodies elicited by d16 effectively cross-reacted with several SARS-CoV-2 *** immunoglobulin A was detected in the blood and nasal wash of vaccinated *** 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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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 *** the multi-functional papain-like protease(PLpro)domain of the viral nsp3 holds ***,none of the known coronavirus PLpro inhibitors has been shown to be in vivo ***,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 *** 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 *** proof-ofconcept findings demonstrated that PLpro is a valid target for the development of broad-spectrum anticoronavirus *** 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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Adult-onset immunodeficiency due to anti-interferon-gammaautoantibody in mainland Chinese

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Chinese Medical Journal 2014年第6期127卷 1189-1190页

作者： jasper fuk-woo chan Kwok-Sang Yee Bone Siu-Fai Tang Vincent Chi-Chung Cheng Ivan Fan-Ngai Hung Kwok-Yung Yuen State Key Laboratory of Emerging Infectious Diseases Department of Microbiology the University of Hong Kong Hong Kong China. Integrated Medical Services Kwong Wah Hospital Hong Kong China. Department of Pathology Hong Kong Sanatorium and Hospital Hong Kong China. Department of Microbiology Queen Mary Hospital Hong Kong China. Department of Medicine the University of Hong Kong Hong Kong China. State Key Laboratory of Emerging Infectious Diseases Department of Microbiology the University of Hong Kong Hong Kong China. Email: kyyuen@hkucc.hku.hk.

Immunodeficiency due to anti-interferon-gamma(anti-IFN-γ)autoantibody is an emerging adult-onsetimmunodeficiency syndrome associated with severeor disseminated infections caused by non-tuberculous

关键词： autoantibody iterferon gamma mycobacterium Penicillium marneffei erythema nodosum

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Identification of novel small-molecule inhibitors of SARS-CoV-2 by chemical genetics

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Acta Pharmaceutica Sinica B 2024年第9期14卷 4028-4044页

作者： Chris Chun-Yiu chan Qian Guo jasper fuk-woo chan Kaiming Tang Jian-Piao Cai Kenn Ka-Heng Chik Yixin Huang Mei Dai Bo Qin Chon Phin Ong Allen Wing-Ho Chu Wan-Mui chan Jonathan Daniel Ip Lei Wen Jessica Oi-Ling Tsang Tong-Yun Wang Yubin Xie Zhenzhi Qin Jianli Cao Zi-Wei Ye Hin Chu Kelvin Kai-Wang To Xing-Yi Ge Tao Ni Dong-Yan Jin Sheng Cui Kwok-Yung Yuen Shuofeng Yuan State Key Laboratory of Emerging Infectious Diseases Carol Yu Centre for InfectionDepartment of MicrobiologySchool of Clinical MedicineLi Ka Shing Faculty of Medicinethe University of Hong KongPokfulamHong Kong SAR 999077China Department of Infectious Diseases and Microbiology the University of Hong Kong-Shenzhen HospitalShenzhen 518000China Centre for Virology Vaccinology and TherapeuticsHong Kong Science and Technology ParkHong Kong SAR 999077China Academician Workstation of Hainan Province Hainan Medical University-the University of Hong Kong Joint Laboratory of Tropical Infectious DiseasesHaikou 571100China School of Biomedical Sciences Li Ka Shing Faculty of Medicinethe University of Hong KongPokfulamHong Kong SAR 999077China NHC Key Laboratory of Systems Biology of Pathogens Institute of Pathogen Biology Chinese Academy of Medical Sciences&Peking Union Medical CollegeBeijing 100730China College of Biology Hunan Provincial Key Laboratory of Medical VirologyHunan UniversityChangsha 410082China

There are only eight approved small molecule antiviral drugs for treating *** them,four are nucleotide analogues(remdesivir,JT001,molnupiravir,and azvudine),while the other four are protease inhibitors(nirmatrelvir,ensitrelvir,leritrelvir,and simnotrelvir-ritonavir).Antiviral resistance,unfavourable drug‒drug interaction,and toxicity have been reported in previous *** there is a dearth of new treatment options for *** this work,a three-tier cell-based screening was employed to identify novel compounds with anti-SARS-CoV-2 *** compound,designated 172,demonstrated broad-spectrum antiviral activity against multiple human pathogenic coronaviruses and different SARS-CoV-2 variants of *** studies validated by reverse genetics showed that compound 172 inhibits the 3-chymotrypsin-like protease(3CLpro)by binding to an allosteric site and reduces 3CLpro dimerization.A drug synergistic checkerboard assay demonstrated that compound 172 can achieve drug synergy with nirmatrelvir in *** vivo studies confirmed the antiviral activity of compound 172 in both Golden Syrian Hamsters and K18 humanized ACE2 ***,this study identified an alternative druggable site on the SARS-CoV-23CLpro,proposed a potential combination therapy with nirmatrelvir to reduce the risk of antiviral resistance and shed light on the development of allosteric protease inhibitors for treating a range of coronavirus diseases.

关键词： SARS-CoV-2 High throughput screening Broad-spectrum antiviral treatment 3CLpro inhibitor Allosteric-site inhibitor Animal models Chemical genetics Reverse genetics

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Clinical Characteristics,Laboratory Identification,and In Vitro Antifungal Susceptibility of Yarrowia(Candida)lipolytica Isolates Causing Fungemia

Clinical Characteristics,Laboratory Identification,and In Vi...

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中华医学会第十二次全国临床微生物学术年会暨第十一次全球华人临床微生物学与感染症学术年会

作者：赵颖 jasper fuk-woo chan Chi-Ching Tsang He Wang Dawen Guo Yuhong Pan Yuling Xiao Na Yue Jonathan Hon-Kwan Chen Susanna Kar-Pui Lau Yingchun Xu Patrick Chiu-Yat woo Department of Clinical Laboratory Peking Union Medical College HospitalChinese Academy of Medical Sciences State Key Laboratory of Emerging Infectious Diseases Department of MicrobiologyResearch Centre of Infection and Immunologyand Carol Yu Centre for InfectionThe University of Hong Kong Department of Microbiology the First Affiliated HospitalHarbin Medical University Department of Clinical Laboratory Fujian Medical University Union Hospital Division of Clinical Microbiology Department of Laboratory MedicineWest China HospitalSichuan University Laboratory Center General Hospital of Tianjin Medical University

目的研究引起真菌血症的解脂念珠菌的相关临床病例特征,实验室鉴定和体外真菌药敏试验。方法对2009-2012年CHIF-NET中分离到的15株解脂念珠菌进行临床病例分析。采用Vitek 2 YSTID Card,API 20C AUX system和MALDI-TOF MS.对菌株进行生...

目的研究引起真菌血症的解脂念珠菌的相关临床病例特征,实验室鉴定和体外真菌药敏试验。方法对2009-2012年CHIF-NET中分离到的15株解脂念珠菌进行临床病例分析。采用Vitek 2 YSTID Card,API 20C AUX system和MALDI-TOF MS.对菌株进行生化鉴定研究。采用Sensititre YeastOne微量肉汤稀释法进行9种抗真菌药物的体外药敏试验。结果这些菌株的临床病例分析提示对于不复杂的解脂念珠菌导管相关性感染可以采用仅移除导管而不

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2000年后中国Q热的临床表现及诊疗研究进展

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中国感染与化疗杂志 2024年第2期24卷 231-239页

作者：邓超文孙林琳叶海燕陈福和邢凡凡香港大学深圳医院感染性疾病医学部感染科广东深圳518000

Q热(Q fever)是贝纳柯克斯体(Coxiella burnetii)感染引起的一种世界性分布的人畜共患病,可累及颅脑、肺脏、肝脏、心脏瓣膜、血管、骨关节等部位。Q热侵入人体网状内皮系统可引起多系统发热性急性或持续性局灶感染,急性感染表现为发热... 详细信息

Q热(Q fever)是贝纳柯克斯体(Coxiella burnetii)感染引起的一种世界性分布的人畜共患病,可累及颅脑、肺脏、肝脏、心脏瓣膜、血管、骨关节等部位。Q热侵入人体网状内皮系统可引起多系统发热性急性或持续性局灶感染,急性感染表现为发热、头痛、肺炎、肝炎等,持续性局灶感染表现为心内膜炎、血管感染、骨髓炎等。由于Q热的临床表现多样、流行病学史资料无特异性、未纳入我国法定传染性疾病、医务工作者对其诊断和治疗方面存在认识不足以及实验室检查方法未被广泛应用等原因,导致误诊和延误诊断时有发生。另一方面,国内关于Q热的研究更多聚焦在畜牧业领域或病例报告,较少有临床或研究工作者对该病进行分析总结。

关键词： Q热贝纳柯克斯体诊断治疗

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Extensive contact tracing and screening to control the spread of vancomycin-resistant Enterococcus faecium ST414 in Hong Kong

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Chinese Medical Journal 2012年第19期125卷 3450-3457页

作者： CHENG Vincent Chi-chung TAI Josepha Wai-ming NG Modissa Lai-ming chan jasper fuk-woo WONG Sally Cheuk-ying LI Iris Wai-sum CHUNG Hon-ping LO Wai-kei YUEN Kwok-yung HO Pak-leung Department of Microbiology Queen Mary Hospital Hong Kong Special Administrative Region China Infection Control Team Queen Mary Hospital Hong Kong Special Administrative Region China Department of Surgery Tung Wah Hospital Hong Kong Special Administrative Region China Infection Control Team Tung Wah Hospital Hong Kong Special Administrative Region China

Background Proactive infection control management is crucial in preventing the introduction of multiple drug resistant organisms in the healthcare setting. In Hong Kong, where vancomycin-resistant enterococci （VRE） endemicity is not yet established, contact tracing and screening, together with other infection control measures are essential in limiting intra- and inter-hospital transmission. The objective of this study was to illustrate the control measures used to eradicate a VRE outbreak in a hospital network in Hong Kong. Methods We described an outbreak of VRE in a healthcare region in Hong Kong, involving a University affiliated hospital and a convalescent hospital of 1600 and 550 beds respectively. Computer-assisted analysis was utilized to facilitate contact tracing, followed by VRE screening using chromogenic agar. Multi-locus sequence typing （MLST） was performed to assess the clonality of the VRE strains isolated. A case-control study was conducted to identify the risk factors for nosocomial acquisition of VRE. Results Between November 26 and December 17, 2011, 11 patients （1 exogenous case and 10 secondary cases） in two hospitals with VRE colonization were detected during our outbreak investigation and screening for 361 contact patients, resulting in a clinical attack rate of 2.8% （10/361）. There were 8 males and 3 females with a median age of 78 years （range, 40-87 years）. MLST confirmed sequence type ST414 in all isolates. Case-control analysis demonstrated that VRE positive cases had a significantly longer cumulative length of stay （P 〈0.001）, a higher proportion with chronic cerebral and cardiopulmonary conditions （P=0.001）, underlying malignancies （P 〈0.001）, and presence of urinary catheter （P 〈0.001）, wound or ulcer （P 〈0.001）, and a greater proportion of these patients were receiving β-lactam/ β-1actamase inhibitors （P=0.009）, carbapenem group （P 〈0.001）, fluoroquinolones （P=0.003）, or vancomycin （P=0.001） when compared with the controls. Conclusion

关键词： vancomycin-resistant Enterococcus faecium ST414 outbreak contact tracing screening

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