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sars-cov-2 immunity in animal models

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 ***-cov-2 infection results in severe respiratory illness and can lead to significant complications in affected *** complications encompass symptoms such as coughing,respiratory distress,fever,infectious shock,acute respiratory distress syndrome(ARDS),and even multiple-organ *** models serve as crucial tools for investigating pathogenic mechanisms,immune responses,immune escape mechanisms,antiviral drug development,and vaccines against ***,various animal models for sars-cov-2 infection,such as nonhuman primates(NHPs),ferrets,hamsters,and many different mouse models,have been *** model possesses distinctive features and *** 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 ***,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

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sars-cov-2 and innate immunity:the good,the bad,and the"goldilocks"

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Cellular & Molecular Immunology 2024年第2期21卷 171-183页

作者： Benjamin L.Sievers Mark T.K.Cheng Kata Csiba Bo Meng Ravindra K.Gupta Department of Medicine University of CambridgeCambridgeUK Cambridge Institute of Therapeutic Immunology&Infectious Disease(CITID) Department of MedicineUniversity of CambridgeCambridgeUk

An ancient conflict between hosts and pathogens has driven the innate and adaptive arms of *** about this interplay can not only help us identify biological mechanisms but also reveal pathogen vulnerabilities that can be leveraged *** humoral response to sars-cov-2 infection has been the focus of intense research,and the role of the innate immune system has received significantly less ***,we review current knowledge of the innate immune response to sars-cov-2 infection and the various means sars-cov-2 employs to evade innate defense *** also consider the role of innate immunity in sars-cov-2 vaccines and in the phenomenon of long covID.

关键词： sars-cov-2 Innate immune response Interferon Cytokines Inflammation Antiviral targets

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Multi-omics analysis of attenuated variant reveals potential evaluation marker of host damaging for sars-cov-2 variants

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Science China(Life Sciences) 2024年第1期67卷 83-95页

作者： Guangshan Xie Lin Zhu Siwen Liu Cun Li Xin Diao Yanhao Zhang Xiuli Su Yuanyuan Song Guodong Cao Li Zhong Pui Wang Xiaojuan Liu Bobo Wing-Yee Mok Shusheng Zhang Dong-Yan Jin Jie Zhou Honglin Chen Zongwei Cai State Key Laboratory of Environmental and Biological Analysis Hong Kong Baptist UniversityHong Kong SARChina State Key Laboratory for Emerging Infectious Diseases and Department of MicrobiologyLi Ka Shing Faculty of MedicineThe University of Hong KongHong Kong SARChina College of Chemistry Zhengzhou UniversityZhengzhou 450001China School of Biomedical Sciences The University of Hong KongHong Kong SARChina HKBU Shenzhen Institute of Research and Continuing Education Shenzhen 518000China

sars-cov-2 continues to threaten human society by generating novel variants via mutation and *** high number of mutations that appeared in emerging variants not only enhanced their immune-escaping ability but also made it difficult to predict the pathogenicity and virulence based on viral nucleotide *** markers for evaluating the pathogenicity of new variants are therefore *** comparing host responses to wild-type and variants with attenuated pathogenicity at proteome and metabolome levels,six key molecules on the polyamine biosynthesis pathway including putrescine,SAM,dc-SAM,ODC1,SAMS,and SAMDC were found to be differentially upregulated and associated with pathogenicity of *** validate our discovery,human airway organoids were subsequently used which recapitulates sars-cov-2 replication in the airway epithelial cells of covID-19 *** ODC1 as a proof-ofconcept,differential activation of polyamine biosynthesis was found to be modulated by the renin-angiotensin system(RAS)and positively associated with ACE2 *** experiments demonstrated that ODC1 expression could be differentially activated upon a panel of sars-cov-2 variants of concern(VOCs)and was found to be correlated with each VOCs’pathogenic ***,the presented study revealed the discriminative ability of key molecules on polyamine biosynthesis as a predictive marker for virulence evaluation and assessment of sars-cov-2 variants in cell or organoid *** work,therefore,presented a practical strategy that could be potentially applied as an evaluation tool for the pathogenicity of current and emerging sars-cov-2 variants.

关键词： sars-cov-2 multi-omics attenuated variant predictive pathogenic marker polyamine biosynthesis

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Ciclopirox inhibits sars-cov-2 replication by promoting the degradation of the nucleocapsid protein

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Acta Pharmaceutica Sinica B 2024年第6期14卷 2505-2519页

作者： Xiafei Wei Yuzheng Zhou Xiaotong Shen Lujie Fan Donglan Liu Xiang Gao Jian Zhou Yezi Wu Yunfei Li Wei Feng Zheng Zhang Institute for Hepatology National Clinical Research Center for Infectious DiseaseShenzhen Third People's HospitalSouthern University of Science and TechnologyShenzhen 518112China Guangzhou Laboratory Guangzhou Medical UniversityGuangzhou 511495China 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

The nucleocapsid protein(NP)plays a crucial role in sars-cov-2 replication and is the most abundant structural protein with a long *** its vital role in severe acute respiratory syndrome coronavirus 2(sars-cov-2)assembly and host inflammatory response,it remains an unexplored target for drug *** this study,we identified a small-molecule compound(ciclopirox)that promotes NP degradation using an FDA-approved library and a drug-screening cell *** significantly inhibited sars-cov-2 replication both in vitro and in vivo by inducing NP *** induced abnormal NP aggregation through indirect interaction,leading to the formation of condensates with higher viscosity and lower *** condensates were subsequently degraded via the autophagy-lysosomal pathway,ultimately resulting in a shortened NP half-life and reduced NP *** results suggest that NP is a potential drug target,and that ciclopirox holds substantial promise for further development to combat sars-cov-2 replication.

关键词： sars-cov-2 Nucleocapsid protein Viral replication Ciclopirox Abnormal aggregation Protein degradation Autophagy-lysosome Drug target

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Mast cell degranulation-triggered by sars-cov-2 induces tracheal-bronchial epithelial inflammation and injury

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Virologica Sinica 2024年第2期39卷 309-318页

作者： Jian-Bo Cao Shu-Tong Zhu Xiao-Shan Huang Xing-Yuan Wang Meng-Li Wu Xin Li Feng-Liang Liu Ling Chen Yong-Tang Zheng Jian-Hua Wang Guangzhou Institutes of Biomedicine and Health Chinese Academy of SciencesGuangzhou 510530China School of Life Sciences and Medicine University of Science and Technology of ChinaHefei 230026China Key Laboratory of Bioactive Peptides of Yunnan Province Key Laboratory of Animal Models and Human Disease Mechanisms of the Chinese Academy of SciencesKIZCUHK Joint Laboratory of Bioresources and Molecular Research in Common DiseasesCenter for Biosafety Mega-ScienceKunming Institute of ZoologyChinese Academy of SciencesKunming 650223China University of Chinese Academy of Sciences Beijing 101408China

sars-cov-2 infection-induced hyper-inflammation is a key pathogenic factor of *** research,along with others',has demonstrated that mast cells(MCs)play a vital role in the initiation of hyper-inflammation caused by *** previous study,we observed that sars-cov-2 infection induced the accumulation of MCs in the peri-bronchus and bronchioalveolar-duct junction in humanized ***,we found that MC degranulation triggered by the spike protein resulted in inflammation in alveolar epithelial cells and capillary endothelial cells,leading to subsequent lung *** trachea and bronchus are the routes for sars-cov-2 transmission after virus inhalation,and inflammation in these regions could promote viral *** are widely distributed throughout the respiratory ***,in this study,we investigated the role of MCs and their degranulation in the development of inflammation in tracheal-bronchial *** analyses showed the accumulation and degranulation of MCs in the peri-trachea of humanized mice infected with *** degranulation caused lesions in trachea,and the formation of papillary hyperplasia was *** transcriptome analysis in bronchial epithelial cells,we found that MC degranulation significantly altered multiple cellular signaling,particularly,leading to upregulated immune responses and *** administration of ebastine or loratadine effectively suppressed the induction of inflammatory factors in bronchial epithelial cells and alleviated tracheal injury in *** together,our findings confirm the essential role of MC degranulation in sars-cov-2-induced hyper-inflammation and the subsequent tissue ***,our results support the use of ebastine or loratadine to inhibit sars-cov-2-triggered degranulation,thereby preventing tissue damage caused by hyper-inflammation.

关键词： sars-cov-2 Mast cell(MC) Bronchial epithelial cell Inflammation Tracheal injury

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Development of an active-site titrant for sars-cov-2 main protease as an indispensable tool for evaluating enzyme kinetics

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Acta Pharmaceutica Sinica B 2024年第5期14卷 2349-2357页

作者： Rabea Voget Julian Breidenbach Tobias Claff Alexandra Hingst Katharina Sylvester Christian Steinebach Lan Phuong Vu Renato H.Weiße Ulrike Bartz Norbert Sträter Christa E.Müller Michael Gütschow Pharmaceutical Institute Pharmaceutical&Medicinal ChemistryUniversity of BonnBonn 53121Germany Institute of Bioanalytical Chemistry Center for Biotechnology and BiomedicineLeipzig UniversityLeipzig 04103Germany Department of Natural Sciences University of Applied Sciences Bonn-Rhein-SiegRheinbach 53359Germany

A titrant for the sars-cov-2 main protease(M^(pro))was developed that enables,for the first time,the exact determination of the concentration of the enzymatically active M^(pro) by active-site *** covalent binding mode of the tetrapeptidic titrant was elucidated by the determination of the crystal structure of the enzyme–titrant *** fluorogenic substrates of M^(pro),including a prototypical,internally quenched Dabcyl-EDANS peptide,were compared in terms of solubility under typical assay *** exploiting the new titrant,key kinetic parameters for the M^(pro)-catalyzed cleavage of these substrates were determined.

关键词： covID-19 sars-cov-2 Main protease Peptide nitriles Fluorogenic substrates Active-site titration X-ray crystallography Inner filter effect

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Role of marine natural products in the development of antiviral agents against sars‑cov‑2:potential and prospects

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Marine Life Science & Technology 2024年第2期6卷 280-297页

作者： D.P.Nagahawatta N.M.Liyanage Thilina U.Jayawardena H.H.A.C.K.Jayawardhana Seong‑Hun Jeong Hyung‑Jun Kwon You‑Jin Jeon Department of Marine Life Sciences Jeju National UniversityJeju 690-756Republic of Korea Department of Chemistry Biochemistry and PhysicsUniversitédu QuébecàTrois-RivièresTrois-RivièresQC G8Z 4M3Canada Marine Science Institute Jeju National UniversityJeju 63333Republic of Korea Functional Biomaterial Research Center Korea Research Institute of Bioscience and BiotechnologyJeongeup-siRepublic of Korea

A novel coronavirus,known as severe acute respiratory syndrome coronavirus 2(sars-cov-2),has surfaced and caused global concern owing to its ***-cov-2 is the causative agent of coronavirus disease 2019;however,it was only discovered at the end of the year and was considered a pandemic by the World Health ***,the develop-ment of novel potent inhibitors against sars-cov-2 and future outbreaks is urgently *** naturally occurring bioactive substances have been studied in the clinical setting for diverse *** intricate infection and replication mechanism of sars-cov-2 offers diverse therapeutic drug targets for developing antiviral medicines by employing natural products that are safer than synthetic *** natural products(MNPs)have received increased attention in the development of novel drugs owing to their high diversity and ***,this review article investigates the infection and replication mechanisms,including the function of the sars-cov-2 genome and ***,we highlighted anti-sars-cov-2 therapeutic intervention efforts utilizing MNPs and predicted sars-cov-2 inhibitor design.

关键词： sars-cov-2 Marine natural products Drug targets Inhibitors

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Two antibodies show broad,synergistic neutralization against sars-cov-2 variants by inducing conformational change within the RBD

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Protein & Cell 2024年第2期15卷 121-134页

作者： Hui Sun Tingting Deng Yali Zhang Yanling Lin Yanan Jiang Yichao Jiang Yang Huang Shuo Song Lingyan Cui Tingting Li Hualong Xiong Miaolin Lan Liqin Liu Yu Li Qianjiao Fang Kunyu Yu Wenling Jiang Lizhi Zhou Yuqiong Que Tianying Zhang Quan Yuan Tong Cheng Zheng Zhang Hai Yu Jun Zhang Wenxin Luo Shaowei Li Qingbing Zheng Ying Gu Ningshao Xia State Key Laboratory of Molecular Vaccinology and Molecular Diagnostics School of Public HealthSchool of Life SciencesXiamen UniversityXiamen 361102China National Institute of Diagnostics and Vaccine Development in Infectious Diseases School of Public HealthSchool of Life SciencesXiamen UniversityXiamen 361102China State Key Laboratory of Vaccines for Infectious Diseases School of Public HealthSchool of Life SciencesXiamen UniversityXiamen 361102China Xiang An Biomedicine Laboratory Xiamen 361102China Institute for Hepatology National Clinical Research Center for Infectious DiseaseShenzhen Third People's HospitalSchool of MedicineSouthem University of Science and TechnologyShenzhen 518112China The Second Affliated Hospital School of MedicineSouthern University of Science and TechnologyShenzhen 518112China Research Unit of Frontier Technology of Structural Vaccinology Chinese Academy of Medical SciencesXiamen 361102China

Continual evolution of the severe acute respiratory syndrome coronavirus(sars-cov-2)virus has allowed for its gradual evasion of neutralizing antibodies(nAbs)produced in response to natural infection or *** rapid nature of these changes has incited a need for the development of superior broad nAbs(bnAbs)and/or the rational design of an antibody cocktail that can protect against the mutated virus ***,we report two angiotensin-converting enzyme 2 competing nAbs—8H12 and 3E2—with synergistic neutralization but evaded by some Omicron ***-electron microscopy reveals the two nAbs synergistic neutralizing virus through a rigorous pairing permitted by rearrangement of the 472-489 loop in the receptor-binding domain to avoid steric *** antibodies based on these two nAbs tremendously extend the neutralizing breadth and restore neutralization against recent variants including currently dominant ***,these findings expand our understanding of the potential strategies for the neutralization of sars-cov-2 variants toward the design of broad-acting antibody therapeutics and vaccines.

关键词： sars-cov-2 broad neutralizing antibody rearrangement synergistic neutralization

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Olfactory immune response to sars-cov-2

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Cellular & Molecular Immunology 2024年第2期21卷 134-143页

作者： Sebastian A.Wellford E.Ashley Moseman Department of Integrative Immunobiology Duke University School of MedicineDurhamNCUSA

Numerous pathogens can infect the olfactory tract,yet the pandemic caused by sars-cov-2 has strongly emphasized the importance of the olfactory mucosa as an immune *** in the nasal passages,the olfactory mucosa is directly exposed to the environment to sense airborne odorants;however,this also means it can serve as a direct route of entry from the outside world into the *** a result,olfactotropic infections can have serious consequences,including dysfunction of the olfactory system,CNS invasion,dissemination to the lower respiratory tract,and transmission between *** research has shown that a distinctive immune response is needed to protect this neuronal and mucosal tissue.A better understanding of innate,adaptive,and structural immune barriers in the olfactory mucosa is needed to develop effective therapeutics and vaccines against olfactotropic microbes such as ***,we summarize the ramifications of sars-cov-2 infection of the olfactory mucosa,review the subsequent immune response,and discuss important areas of future research for olfactory immunity to infectious disease.

关键词： Mucosal immunology Neuroimmunology Infectious Disease sars-cov-2

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B-cell and antibody responses to sars-cov-2:infection,vaccination,and hybrid immunity

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Cellular & Molecular Immunology 2024年第2期21卷 144-158页

作者： Dennis Lapuente Thomas H.Winkler Matthias Tenbusch Institut für klinische und molekulare Virologie Universitätsklinikum Erlangen und Friedrich-Alexander-Universität(FAU)Erlangen-NürnbergSchlossgarten 491054 ErlangenGermany Department of Biology Division of GeneticsNikolaus-Fiebiger-Center for Molecular MedicineFriedrich-Alexander-Universität Erlangen-Nürnberg(FAU)ErlangenGermany Medical Immunology Campus Erlangen Friedrich-Alexander-Universität(FAU)Erlangen-NürnbergSchlossplatz 191054 ErlangenGermany

The emergence of severe acute respiratory syndrome coronavirus 2(sars-cov-2)in 2019 prompted scientific,medical,and biotech communities to investigate infection-and vaccine-induced immune responses in the context of this pathogen.B-cell and antibody responses are at the center of these investigations,as neutralizing antibodies(nAbs)are an important correlate of protection(COP)from infection and the primary target of sars-cov-2 vaccine *** addition to absolute levels,nAb longevity,neutralization breadth,immunoglobulin isotype and subtype composition,and presence at mucosal sites have become important topics for scientists and health policy *** recent pandemic was and still is a unique setting in which to study de novo and memory B-cell(MBC)and antibody responses in the dynamic interplay of infection-and vaccine-induced *** also provided an opportunity to explore new vaccine platforms,such as mRNA or adenoviral vector vaccines,in unprecedented cohort *** with the technological advances of recent years,this situation has provided detailed mechanistic insights into the development of B-cell and antibody responses but also revealed some unexpected *** this review,we summarize the key findings of the last 2.5 years regarding infection-and vaccine-induced B-cell immunity,which we believe are of significant value not only in the context of sars-cov-2 but also for future vaccination approaches in endemic and pandemic settings.

关键词： sars-cov-2 neutralizing antibodies memory responses vaccines IgG4

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