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SARS-CoV-2 immunity in animal models

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Cellular & Molecular Immunology 2024年第2期21卷 119-133页

作者： zhao Chen Yaochang Yuan Qingtao Hu Airu Zhu Fenghua Chen Shu Li Xin Guan Chao Lv Tian Tang Yiyun He Jinling Cheng Jie Zheng Xiaoyu Hu jingxian zhao Jincun zhao Jing Sun State Key Laboratory of Respiratory Disease National Clinical Research Centre for Respiratory DiseaseNational Centre for Respiratory MedicineGuangzhou Institute of Respiratory Healththe First Affiliated Hospital of Guangzhou Medical UniversityGuangzhouGuangdong 510182China GMU-GIBH Joint School of Life Sciences Guangzhou Medical UniversityGuangzhou 510000China Guangzhou National Laboratory GuangzhouGuangdong 510005China Shanghai Institute for Advanced Immunochemical Studies School of Life Science and TechnologyShanghaiTech UniversityShanghai 201210China Institute for Hepatology National Clinical Research Center for Infectious DiseaseShenzhen Third People’s Hospitalthe Second Affiliated HospitalSchool of MedicineSouthern University of Science and TechnologyShenzhen 518005China

The COVID-19 pandemic,which was caused by severe acute respiratory syndrome coronavirus 2(SARS-CoV-2),has become a worldwide health crisis due to its transmissibility.SARS-CoV-2 infection results in severe respiratory illness and can lead to significant complications in affected individuals.These complications encompass symptoms such as coughing,respiratory distress,fever,infectious shock,acute respiratory distress syndrome(ARDS),and even multiple-organ failure.Animal models serve as crucial tools for investigating pathogenic mechanisms,immune responses,immune escape mechanisms,antiviral drug development,and vaccines against SARS-CoV-2.Currently,various animal models for SARS-CoV-2 infection,such as nonhuman primates(NHPs),ferrets,hamsters,and many different mouse models,have been developed.Each model possesses distinctive features and applications.In this review,we elucidate the immune response elicited by SARS-CoV-2 infection in patients and provide an overview of the characteristics of various animal models mainly used for SARS-CoV-2 infection,as well as the corresponding immune responses and applications of these models.A comparative analysis of transcriptomic alterations in the lungs from different animal models revealed that the K18-hACE2 and mouse-adapted virus mouse models exhibited the highest similarity with the deceased COVID-19 patients.Finally,we highlighted the current gaps in related research between animal model studies and clinical investigations,underscoring lingering scientific questions that demand further clarification.

关键词： COVID-19 SARS-CoV-2 animal models immune response

Successful clearance of persistent SARS-CoV-2 asymptomatic infection following a single dose of Ad5-nCoV vaccine

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Signal Transduction and Targeted Therapy 2023年第4期8卷 1942-1952页

作者： Shaofu Qiu zhao Chen Airu Zhu Qiuhui Zeng Hongbo Liu Xiaoqing Liu Feng Ye Yingkang Jin Jie Wu Chaojie Yang Qi Wang Fangli Chen Lan Chen Sai Tian Xinying Du Qingtao Hu Jinling Cheng Canjie Chen Fang Li Jing Sun Yanqun Wang jingxian zhao Jincun zhao Hongbin Song The Chinese PLA Center for Disease Control and Prevention 100071 BeijingChina State Key Laboratory of Respiratory Disease National Clinical Research Centre for Respiratory DiseaseGuangzhou Institute of Respiratory Healththe First Affiliated Hospital of Guangzhou Medical University510182 GuangzhouGuangdongChina Pediatric Pulmonary Department Guangzhou Women and Children’s Medical CenterGuangzhou Medical University510623 GuangzhouGuangdongChina Guangdong Provincial Center for Disease Control and Prevention 510399 GuangzhouGuangdongChina Guangzhou Laboratory Bio-island510320 GuangzhouGuangdongChina Institute of Infectious Disease Guangzhou Eighth People’s Hospital of Guangzhou Medical University510060 GuangzhouGuangdongChina Shanghai Institute for Advanced Immunochemical Studies School of Life Science and TechnologyShanghaiTech University201210 ShanghaiChina National Clinical Research Center for Infectious Disease Shenzhen Third People’s HospitalThe Second Affiliated HospitalSchool of MedicineSouthern University of Science and Technology518112 ShenzhenGuangdongChina

Persistent asymptomatic(PA)SARS-CoV-2 infections have been identified.The immune responses in these patients are unclear,and the development of effective treatments for these patients is needed.Here,we report a cohort of 23 PA cases carrying viral RNA for up to 191 days.PA cases displayed low levels of inflammatory and interferon response,weak antibody response,diminished circulating follicular helper T cells(cTfh),and inadequate specific CD4+and CD8+T-cell responses during infection,which is distinct from symptomatic infections and resembling impaired immune activation.Administration of a single dose of Ad5-nCoV vaccine to 10 of these PA cases elicited rapid and robust antibody responses as well as coordinated B-cell and cTfh responses,resulting in successful viral clearance.Vaccine-induced antibodies were able to neutralize various variants of concern and persisted for over 6 months,indicating long-term protection.Therefore,our study provides an insight into the immune status of PA infections and highlights vaccination as a potential treatment for prolonged SARS-CoV-2 infections.

关键词： infection impaired asymptomatic

Immune responses to SARS-CoV-2 infection in Humans and ACE2 humanized mice

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Fundamental Research 2021年第2期1卷 124-130页

作者： Airu Zhu zhao Chen Yanqun Wang Qiuhui Zeng Jing Sun Zhen Zhuang Fang Li jingxian zhao Jincun zhao Nanshan Zhong State Key Laboratory of Respiratory Disease National Clinical Research Center for Respiratory DiseaseGuangzhou Institute of Respiratory Healththe First Affiliated Hospital of Guangzhou Medical UniversityGuangzhouGuangdong 510120China

The coronavirus disease 2019(COVID-19)pandemic caused by severe acute respiratory syndrome coronavirus 2(SARS-CoV-2)represents a major public health threat worldwide.Insight into protective and pathogenic aspects of SARS-CoV-2 immune responses is critical to work out effective therapeutics and develop vaccines for controlling the disease.Here,we review the present literature describing the innate and adaptive immune responses including innate immune cells,cytokine responses,antibody responses and T cell responses against SARS-CoV-2 in human infection,as well as in AEC2-humanized mouse infection.We also summarize the now known and unknown about the role of the SARS-CoV-2 immune responses.By better understanding the mechanisms that drive the immune responses,we can tailor treatment strategies at specific disease stages and improve our response to this worldwide public health threat.

关键词： SARS-CoV-2 Innate immune response Humoral immune responses T cell response Mouse model

Genetic and pathogenicity diversity of dengue virus type 2 strains circulating in Guangdong,China

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Biosafety and Health 2021年第6期3卷 333-342页

作者： Lu Zhang Lingzhai zhao zhaoyong Zhang Wenxin Hong Jian Wang Shuang Qiu Huiqin Yang Mian Gan Jing Sun jingxian zhao Yanqun Wang Jincun zhao Fuchun Zhang Institute of Infectious Disease Guangzhou Eighth People's Hospital of Guangzhou Medical UniversityGuangzhou 510120China Technology Center Guangzhou CustomsGuangzhou 510120China State Key Laboratory of Respiratory Disease National Clinical Research Center for Respiratory DiseaseGuangzhou Institute of Respiratory Healththe First Affiliated Hospital of Guangzhou Medical UniversityGuangzhou 510120China

Dengue fever is a mosquito-borne viral disease spread in tropical and subtropical regions caused by the dengue virus(DENV).DENV causes a febrile illness,severe forms including hemorrhagic fevers and shock with fatalities in humans.DENV-2 is frequently associated with severe dengue infections and epidemics.DENV-2 strains from Guangdong,China,have not been characterized to compare the phylogenetics and pathogenicity of different DENV-2 subgenotype strains in both vitro and vivo.A total of 22 patients tested to be DENV-2 positive and were enrolled in this study,22 complete genomes were obtained by virus isolation and high-throughput sequencing.Phylogenetic and single amino polymorphism(SAP)analysis indicated that two major subgenotypes(A and C)of DENV-2 Cosmopolitan were prevalent in Guangdong in 2018.The apparent change of major subgenotypes of DENV-2 circulating in Guangdong indicated the diversity of DENV-2 strains,including endemic genotype and imported genotype.It alerted the risk of cross-border transmission of DENV.A significant difference in replication rate was observed in C6/36 between different DENV-2 strains,although growth kinetics comparison of different DENV-2 Cosmopolitan subgenotypes showed similar profiles.DENV-2 subgenotypes(A and C)replicated efficiently in IFNAR−/−C57BL/6 mice,and subgenotype A of Cosmopolitan infected mice showed increased weight loss and delayed viral clearance compared with the subgenotype C group.DENV-2 prevalent in Guangdong in 2018 showed apparent genetic and pathogenicity diversity in both vitro and vivo,indicating the necessity of molecular surveillance and exploration of the relationship between its pathogenicity and clinical characteristics.

关键词： DENV-2 Genetic Pathogenicity Diversity

A Phenotyping Protocol for Detailed Evaluation of Apple Root Resistance Responses Utilizing Tissue Culture Micropropagated Apple Plants

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American Journal of Plant Sciences 2018年第11期9卷 2183-2204页

作者： Yanmin Zhu Melody Saltzgiver jingxian zhao United States Department of Agriculture Agricultural Research Service Tree Fruit Research Laboratory Wenatchee WA USA Hebei Academy of Forestry Shijiazhuang China

In the post-genomics era, reliable phenotypes are considered the bottleneck for unraveling the genetic control over the biology of interest. Phenotyping resistance response of roots to infection by soilborne pathogen is more challenging compared to that of plant aerial parts. In additional to the hidden nature and small stature of fine roots where infection occurs, extra obstacles exist for rosaceae tree crops such as apple. Due to self-incompatible reproduction and high-level heterozygosity of apple genome, genetically identical apple plants cannot be produced through apple seed germination. Here we report an established phenotyping protocol which includes a streamlined tissue culture procedure for micropropagation of uniform apple plants, standardized inoculation procedure using Pythium ultimum, and multilayered evaluating methods on apple root resistance traits. Because of the implementation of tissue culture based micropropagation procedure, constant availability of the uniform plants with defined genetic background, equivalent age and non-contaminated roots overcame a longstanding barrier of systematic and detailed phenotypic characterization of apple root resistance traits. Repeated infection assays by root-dipping inoculation demonstrated the reproducible and wide-range plant survival rates, from single-digit to over 90% survived plants for a given genotype. Genotype-specific values due to P. ultimum inoculation on shoot and root biomass reduction, maximum root lengths, leaf number and cumulative leaf areas were quantified between mock-inoculated and P. ultimum infected plants. Use of a glass-box container offered enhanced accessibility and minimized invasiveness for continuous and non-disruptive observation on the necrosis progression patterns along inoculated roots. With the assistance of a dissecting microscope, the genotype-specific resistance responses along the infected apple roots were captured and analyzed in detail. This reported phenotyping protocol represents a major development and should be ea

关键词： Tissue Culture Micropropagation Apple Rootstocks Root Resistance Responses Phenotyping Methods

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

Multi-platform omics analysis reveals molecular signature for COVID-19 pathogenesis,prognosis and drug target discovery

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Signal Transduction and Targeted Therapy 2021年第5期6卷 1535-1545页

作者： Yuming Li Guixue Hou Haibo Zhou Yanqun Wang Hein Min Tun Airu Zhu jingxian zhao Fei Xiao Shanwen Lin Dongdong Liu Dunrong Zhou Lang Mai Lu Zhang zhaoyong Zhang Lijun Kuang Jiao Guan Qiushi Chen Liyan Wen Yanjun Zhang Jianfen Zhuo Fang Li Zhen Zhuang zhao Chen Ling Luo Donglan Liu Chunke Chen Mian Gan Nanshan Zhong Jincun zhao Yan Ren Yonghao Xu State Key Laboratory of Respiratory Disease National Clinical Research Center for Respiratory DiseaseGuangzhou Institute of Respiratory Healththe First Affiliated Hospital of Guangzhou Medical UniversityGuangzhouChina BGI-Shenzhen ShenzhenChina The Sixth Affiliated Hospital of Guangzhou Medical University Qingyuan People's HospitalQingyuanGuangdongChina HKU-Pasteur Research Pole School of Public HealthLi Ka Shing Faculty of MedicineThe University of Hong KongHong Kong SARChina Department of Infectious Diseases Guangdong Provincial Key Laboratory of Biomedical ImagingGuangdong Provincial Engineering Research Center of Molecular ImagingThe Fifth Affiliated HospitalSun Yat-sen UniversityZhuhaiGuangdongChina Yangjiang People's Hospital YangjiangGuangdongChina Yangjiang Center for Disease Control and Prevention YangjiangGuangdongChina Guangzhou Eighth People's Hospital of Guangzhou Medical University GuangzhouGuangdongChina Guangzhou Customs District Technology Center GuangzhouChina

Disease progression prediction and therapeutic drug target discovery for Coronavirus disease 2019(COVID-19)are particularly important,as there is still no effective strategy for severe COVID-19 patient treatment.Herein,we performed multi-platform omics analysis of serial plasma and urine samples collected from patients during the course of COVID-19.Integrative analyses of these omics data revealed several potential therapeutic targets,such as ANXA1 and CLEC3B.Molecular changes in plasma indicated dysregulation of macrophage and suppression of T cell functions in severe patients compared to those in non-severe patients.Further,we chose 25 important molecular signatures as potential biomarkers for the prediction of disease severity.The prediction power was validated using corresponding urine samples and plasma samples from new COVID-19 patient cohort,with AUC reached to 0.904 and 0.988,respectively.In conclusion,our omics data proposed not only potential therapeutic targets,but also biomarkers for understanding the pathogenesis of severe COVID-19.

关键词： pathogenesis urine drug

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花椒越冬抗寒机理研究进展

河北林业科技 2024年第1期 53-56页

作者：李莹秦素洁郭伟珍赵京献孙浩河北省林业和草原科学研究院/河北省林木良种技术创新中心河北石家庄050061 河北科技师范学院河北秦皇岛066000

低温是花椒引种及规模化栽培的限制性因素,且近年来极端天气频繁发生,容易导致花椒受冻甚至死亡。该文从膜脂过氧化及膜保护系统、水分及渗透调节物质、内源激素含量等方面阐述了花椒在冬季低温条件下的生理变化,以及当前对一些花椒品... 详细信息

低温是花椒引种及规模化栽培的限制性因素,且近年来极端天气频繁发生,容易导致花椒受冻甚至死亡。该文从膜脂过氧化及膜保护系统、水分及渗透调节物质、内源激素含量等方面阐述了花椒在冬季低温条件下的生理变化,以及当前对一些花椒品种抗寒性评价的研究结果,总结了目前生产上主要应用的防寒措施,为生产和科研提供参考。

关键词：花椒抗寒性膜脂过氧化渗透调节物质内源激素

大口黑鲈源豚鼠气单胞菌的分离鉴定及全基因组分析

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中国畜牧兽医 2024年第4期51卷 1706-1716页

作者：王迎平赵静贤尚佳富郝成森左妤祺朱桓奕冯旭东徐婷婷倪兴维刘霞杨晓伟曹蓝云张立武谭昌藩曹礼静赵光伟西南大学动物医学院重庆402460 贵州省动物疫病预防控制中心贵阳550008 重庆三杰众鑫生物工程有限公司重庆402460 重庆市巫山县职业教育中心重庆404799 重庆市荣昌区职业教育中心重庆402460

【目的】探究患病大口黑鲈的致病菌及其主要生物学特性,为临床疾病防控提供技术支撑。【方法】首先对发病大口黑鲈进行病理组织学观察,进而利用平板划线法分离细菌,通过革兰染色、生化试验和16S rDNA序列测定对分离菌进行鉴定,通过致病... 详细信息

【目的】探究患病大口黑鲈的致病菌及其主要生物学特性,为临床疾病防控提供技术支撑。【方法】首先对发病大口黑鲈进行病理组织学观察,进而利用平板划线法分离细菌,通过革兰染色、生化试验和16S rDNA序列测定对分离菌进行鉴定,通过致病性试验观察分离菌对小鼠主要脏器造成的病理损伤;而后分别利用PCR方法和Kirby-Bauer(K-B)纸片法对分离菌的常见毒力基因和耐药特征进行检测分析;最后利用二代测序技术绘制其全基因组草图,并通过生物信息学方法对其分子特征进行解析。【结果】自然感染大口黑鲈肝细胞肿大,空泡变性,肠黏膜下层出血,肠壁坏死;于患病黑鲈体内分离到1株优势菌,在血平板上呈乳白色,半透明,直径约1 mm的小菌落,呈β溶血,革兰染色为阴性短杆菌,两端钝圆,经生化试验和16S rDNA测序证实分离菌为豚鼠气单胞菌(Aeromonas caviae),将其命名为SCMS。试验小鼠接种后24 h内死亡率为100%,病理特征与自然感染大口黑鲈相似;SCMS株中共检测到9种毒力基因,分别为Aha、Ahp、Aer、Alt、gcaT、Act、Exu、Ela和eprCAI;药敏试验结果显示,分离菌对大多数四环素类、大环内酯类药物表现耐药或中度敏感;全基因组测序显示,分离菌全长4329602 bp,GC含量为61.5%,基因组信息在GenBank中的登录号为JARFUQ000000000,相似性分析显示分离菌与人源、食品源豚鼠气单胞菌具有高度相似性;病原毒力因子数据库(VFDB)比对显示,分离菌携带多种与黏附、侵入及分泌系统相关的毒力基因;耐药基因数据库(CGE)分析显示,菌株中携带7种耐药基因,部分基因与耐药表型存在不一致的现象。【结论】本试验通过全基因组测序技术解析了1株大口黑鲈源豚鼠气单胞菌的毒力基因和耐药基因,其结果可为大口黑鲈临床疾病防控提供技术支撑。

关键词：大口黑鲈豚鼠气单胞菌全基因组测序毒力基因耐药基因