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sars-cov-2 treatment effects induced by ACE2-expressing microparticles are explained by the oxidized cholesterolincreased endosomal pH of alveolar macrophages

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Cellular & Molecular Immunology 2022年第2期19卷 210-221页

作者： Zhenfeng Wang Jiadi Lv Pin Yu Yajin Qu Yabo Zhou Li Zhou Qiangqiang Zhu Shunshun Li Jiangping Song Wei Deng Ran Gao Yuying Liu Jiangning Liu Wei-Min Tong Chuan Qin Bo Huang Department of Immunology&National Key Laboratory of Medical Molecular Biology Institute of Basic Medical SciencesChinese Academy of Medical Sciences(CAMS)&Peking Union Medical CollegeBeijing 100005China NHC Key Laboratory of Human Disease Comparative Medicine Beijing Key Laboratory for Animal Models of Emerging and Remerging Infectious DiseasesInstitute of Laboratory Animal ScienceCAMS and Comparative Medicine CenterPeking Union Medical CollegeBeijingChina State Key Laboratory of Cardiovascular Disease Fuwai HospitalNational Center for Cardiovascular DiseasesCAMS and Peking Union Medical CollegeBeijingChina Department of Pathology Institute of Basic Medical SciencesCAMS and Peking Union Medical CollegeBeijingChina Department of Biochemistry&Molecular Biology Tongji Medical CollegeHuazhong University of Science&TechnologyWuhan 430030China

Exploring the cross-talk between the immune system and advanced biomaterials to treat sars-cov-2 infection is a promising ***,we show that ACE2-overexpressing A549 cell-derived microparticles(AO-MPs)are a potential therapeutic agent against sars-cov-2 *** administered AO-MPs dexterously navigate the anatomical and biological features of the lungs to enter the alveoli and are taken up by alveolar macrophages(AMs).Then,AO-MPs increase the endosomal pH but decrease the lysosomal pH in AMs,thus escorting bound sars-cov-2 from phago-endosomes to lysosomes for *** pH regulation is attributable to oxidized cholesterol,which is enriched in AO-MPs and translocated to endosomal membranes,thus interfering with proton pumps and impairing endosomal *** addition to promoting viral degradation,AO-MPs also inhibit the proinflammatory phenotype of AMs,leading to increased treatment efficacy in a sars-cov-2-infected mouse model without side *** findings highlight the potential use of AO-MPs to treat sars-cov-2-infected patients and showcase the feasibility of MP therapies for combatting emerging respiratory viruses in the future.

关键词： sars-cov-2 microparticles Alveolar macrophages Endosomes Lysosomes

sars-cov-2 virus NSP14 Impairs NRF2/HMOX1 activation by targeting Sirtuin 1

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Cellular & Molecular Immunology 2022年第8期19卷 872-882页

作者： Shilei Zhang Jingfeng Wang Lulan Wang Saba Aliyari Genhong Cheng Department of Microbiology Immunologyand Molecular GeneticsUniversity of CaliforniaLos AngelesLos Angeles90095CAUSA

Most deaths from the covID-19 pandemic are due to acute respiratory distress syndrome(ARDS)-related respiratory *** storms and oxidative stress are the major players in ARDS development during respiratory virus ***,it is still unknown how oxidative stress is regulated by viral and host factors in response to sars-cov-2 ***,we found that activation of NRF2/HMOX1 significantly suppressed sars-cov-2 replication in multiple cell types by producing the metabolite biliverdin,whereas sars-cov-2 impaired the NRF2/HMOX1 axis through the action of the nonstructural viral protein ***,NSP14 interacts with the catalytic domain of the NAD-dependent deacetylase Sirtuin 1(SIRT1)and inhibits its ability to activate the NRF2/HMOX1 ***,both genetic and pharmaceutical evidence corroborated the novel antiviral activity of SIRT1 against ***,our findings reveal a novel mechanism by which sars-cov-2 dysregulates the host antioxidant defense system and emphasize the vital role played by the SIRT1/NRF2 axis in host defense against sars-cov-2.

关键词： sars-cov-2 NRF2 HMOX1 NSP14 SIRT1 Oxidative stress

sars-cov-2 impairs the disassembly of stress granules and promotes ALS-associated amyloid aggregation

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Protein & Cell 2022年第8期13卷 602-614页

作者： Yichen Li Shuaiyao Lu Jinge Gu Wencheng Xia Shengnan Zhang Shenqing Zhang Yan Wang Chong Zhang Yunpeng Sun Jian Lei Cong Liu Zhaoming Su Juntao Yang Xiaozhong Peng Dan Li Bio-X Institutes Key Laboratory for the Genetics of Developmental and Neuropsychiatric DisordersMinistry of EducationShanghai Jiao Tong UniversityShanghai 200030China School of Life Sciences and Biotechnology Shanghai Jiao Tong UniversityShanghai 200030China National Kunming High-level Biosafety Primate Research Center Institute of Medical BiologyChinese Academy of Medical Sciences and Peking Union Medical CollegeKunming 650031China State Key Laboratory of Medical Molecular Biology Chinese Academy of Medical SciencesSchool of Basic MedicinePeking Union Medical CollegeBeijing 100005China State Key Laboratory of Medical Molecular Biology Department of Biochemistry and Molecular BiologyInstitute of Basic Medical SciencesChinese Academy of Medical Sciences&Peking Union Medical CollegeBeijing 100005China Interdisciplinary Research Center on Biology and Chemistry Shanghai Institute of Organic ChemistryChinese Academy of SciencesShanghai 201210China University of Chinese Academy of Sciences Beijing 100049China State Key Laboratory of Biotherapy Department of Geriatrics and National Clinical Research Center for GeriatricsWest China HospitalSichuan UniversitChengdu 610041China Bio-X-Renji Hospital Research Center Renji HospitalSchool of MedicineShanghai Jiao Tong UniversityShanghai 200240China Zhangjiang Institute for Advanced Study Shanghai Jiao Tong UniversityShanghai 200240China

The nucleocapsid(N)protein of sars-cov-2 has been reported to have a high ability of liquid-liquid phase separation,which enables its incorporation into stress granules(SGs)of host ***,whether SG invasion by N protein occurs in the scenario of sars-cov-2 infection is unknow,neither do we know its ***,we used sars-cov-2 to infect mam-malian cells and observed the incorporation of N protein into SGs,which resulted in markedly impaired self-dis-assembly but stimulated cell cellular clearance of *** experiments further showed that N protein binds to the SG-related amyloid proteins via non-specific tran-sient interactions,which not only expedites the phase transition of these proteins to aberrant amyloid aggre-gation in vitro,but also promotes the aggregation of FUS with ALS-associated P525L mutation in *** addition,we found that ACE2 is not necessary for the infection of sars-cov-2 to mammalian *** work indicates that sars-cov-2 infection can impair the dis-assembly of host SGs and promote the aggregation of SG-related amyloid proteins,which may lead to an increased risk of neurodegeneration.

关键词： sars-cov-2 nucleocapsid protein stress granule

sars-cov-2 cell entry and targeted antiviral development

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Acta Pharmaceutica Sinica B 2021年第12期11卷 3879-3888页

作者： Zinuo Chen Ruikun Du Jazmin M.Galvan Achi Lijun Rong Qinghua Cui College of Pharmacy Shandong University of Traditional Chinese MedicineJinan 250355China Qingdao Academy of Chinese Medicinal Sciences Shandong University of Traditional Chinese MedicineQingdao 266122China Experimental Center Shandong University of Traditional Chinese MedicineJinan 250355China Department of Microbiology and Immunology College of MedicineUniversity of Illinois at ChicagoChicagoIL 60612USA

Severe acute respiratory syndrome coronavirus 2(sars-cov-2)is the causative agent of the pandemic coronavirus disease 2019(covID-19),which threatens human health and public *** the urgent campaign to develop anti-S ARS-cov-2 therapies,the initial entry step is one of the most appealing *** this review,we summarize the current understanding of sars-cov-2 cell entry,and the development of targeted antiviral ***,we speculate upon future directions toward nextgeneration of sars-cov-2 entry inhibitors during the upcoming post-pandemic era.

关键词： sars-cov-2 Cell entry Spike protein Antiviral development Post-pandemic

sars-cov-2 infection in infants under 1 year of age in Wuhan City, China

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World Journal of Pediatrics 2020年第3期16卷 260-266页

作者： Dan Sun Xue Chen Hui Li Xiao-Xia Lu Han Xiao Fu-Rong Zhang Zhi-Sheng Liu Department of Neurology Wuhan Children's HospitalTongji Medical CollegeHuazhong University of Science and TechnologyWuhanHubeiChina Department of Hematology Wuhan Children's HospitalTongji Medical CollegeHuazhong University of Science and TechnologyWuhanHubeiChina Department of Respiratory Diseases Wuhan Children's HospitalTongji Medical CollegeHuazhong University of Science and TechnologyWuhanChina Institute of Maternal and Child Health Wuhan Children's HospitalTongji Medical CollegeHuazhong University and TechnologyWuhanChina Department of Intensive Care Unit Wuhan Children's HospitalTongji Medical CollegeHuazhong University of Science and TechnologyWuhanChina

Background The clinical characteristics and outcome of covID-19 in children are different from those in *** aimed to describe the characteristics of infants under 1 year of age (excluding newborns) with *** We retrospectively retrieved data of 36 infants with sars-cov-2 infection in Wuhan Children's Hospital from January 26 to March 22,*** features,chest imaging findings,laboratory tests results,treatments and clinical outcomes were *** The mean age of the infected infants was 6.43 months,with a range of 2-12 months.61.11% of the patients were males and 38.89% females.86.11% of the infants were infected due to family *** (77.78%) and fever (47.22%) were the most common clinical *** CT scan revealed 61.11% bilateral pneumonia and 36.11% unilateral pneumonia.47.22% of the infants developed *** leucocytes,neutrophils,lymphocytes,and thrombocytes were observed in 11.11,8.33,36.11 and 44.44% of infants,*** leucocytes,neutrophils,thrombocyte and hemoglobin were observed in 8.33,19.44,2.78 and 36.11% of infants,*** C-reactive protein,procalcitonin,lactate dehydrogenase,alanine aminotransferase,creatine kinase and D-dimer were observed in 19.44,67.74,47.22,19.44,22.22 and 20.69% of infants,*** one infant had a high level of ***-infections with other respiratory pathogens were observed in 62.86% of ***3 (20.69%),CD4 (68.97%),CD19 (31.03%) and Th/Ts (44.83%) were elevated;CD8 (6.9%) and CD16+CD56 (48.28%) was ***-4 (7.69%),IL-6 (19.23%),IL-10 (50%),TNF-α (11.54%) and IFN-γ (19.23%) were *** to March 22,97.22% of infants recovered,while a critical ill infant *** the infant's condition deteriorates rapidly,lymphocytopenia was ***,C-reactive protein,D-dimer,alanine aminotransferase,creatine kinase,creatinine,IL-6 and IL-10 increased *** In the cohort,we discover

关键词： covID-19 Coronavirus infant infection sars-cov-2

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 ***-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

sars-cov-2 spike protein as a bacterial lipopolysaccharide delivery system in an overzealous inflammatory cascade

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Journal of Molecular Cell Biology 2022年第9期14卷 26-39页

作者： Firdaus Samsudin Palur Raghuvamsi Ganna Petruk Manoj Puthia Jitka Petrlova Paul MacAry Ganesh S.Anand Peter J.Bond Artur Schmidtchen Bioinformatics Institute(BIl) Agency for ScienceTechnology and Research(A*STAR)Singapore 138671Singapore Department of Biological Sciences National University of SingaporeSingapore 117543Singapore Division of Dermatology and Venereology Department of Clinical SciencesLund UniversitySE-22184 LundSweden Life Sciences Institute Centre for Life SciencesNational University of SingaporeSingapore 117546Singapore Department of Chemistry The Pennsylvania State UniversityPA 16801USA Copenhagen Wound Healing Center Bispebjerg HospitalDepartment of Biomedical SciencesUniversity of CopenhagenDK-2400 CopenhagenDenmark

Accumulating evidence indicates a potential role for bacterial lipopolysaccharide(LPs)in the overactivation of the immune response during sars-cov-2 *** is recognized by Toll-like receptor 4,mediating proinflammatory *** previously reported that LPS directly interacts with sars-cov-2 spike(S)protein and enhances proinflammatory *** native gel electrophoresis and hydrogen-deuterium exchange mass spectrometry,we showed that LPS binds to multiple hydrophobic pockets spanning both the S1 and S2 subunits of the S *** simulations validated by a microscale thermophoresis binding assay revealed that LPS binds to the S2 pocket with a lower affinity compared to S1,suggesting a role as an intermediate in LPS ***,nuclear factor-kappa B(NF-kB)activation in monocytic THP-1 cells is strongly boosted by *** NF-kB reporter mice followed by bioimaging,a boosting effect was observed for both S1 and S2,with the former potentially facilitated by *** Omicron S variant binds to LPS,but with reduced affinity and LPS boosting in vitro and in *** together,the data provide a molecular mechanism by which S protein augments LPS-mediated hyperinflammation.

关键词： covID-19 sars-cov-2 spike protein lipopolysaccharide TLR4 hyperinflammation

sars-cov-2 ORF10 hijacking ubiquitination machinery reveals potential unique drug targeting sites

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Acta Pharmaceutica Sinica B 2024年第9期14卷 4164-4173页

作者： Kaixiang Zhu Lili Song Linyue Wang Lei Hua Ziyu Luo Tongyun Wang Bo Qin Shuofeng Yuan Xiaopan Gao Wenyi Mi Sheng Cui NHC Key Laboratory of Systems Biology of Pathogens National Institute of Pathogen BiologyChinese Academy of Medical Sciences and Peking Union Medical CollegeBeijing 100730China Key Laboratory of Pathogen Infection Prevention and Control(Peking Union Medical College) Ministry of EducationBeijing 100730China The Province and Ministry Co-Sponsored Collaborative Innovation Center for Medical Epigenetics Key Laboratory of Immune Microenvironment and Disease(Ministry of Education)Tianjin Medical University General HospitalDepartment of ImmunologyTianjin Medical UniversityTianjin 300070China Medical School Yan’an UniversityShaanxi ProvinceYan’an 716000China 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

Viruses often manipulate ubiquitination pathways to facilitate their replication and ***2ZYG11B known as the substrate receptor of cullin-2 RING E3 ligase,is bound by sars-cov-2 ORF10 to increase its E3 ligase activity,leading to degradation of IFT46,a protein component of the intraflagellar transport(IFT)complex *** results in dysfunctional cilia,which explains certain symptoms that are specific to ***,the precise molecular mechanism of how ORF10 recognizes CUL2ZYG11B remains ***,we determined the crystal structure of CUL2ZYG11B complexed with the N-terminal extension(NTE)of sars-cov-2 ORF10(2.9 A°).The structure reveals that the ORF10 N-terminal heptapeptide(NTH)mimics the Gly/N-degron to bind *** studies identified key residues within ORF10 that are key players in its interaction with CUL2ZYG11B both in ITC assay and in vivo *** addition,we prove that enhancement of CUL2ZYG11B activity for IFT46 degradation by which ORF10-mediated correlates with the binding affinity between ORF10 and ***,we used a Global Protein Stability system to show that the NTH of ORF10 mimics the Gly/N-degron motif,thereby binding competitively to CUL2ZYG11B and inhibiting the degradation of target substrates bearing the Gly/N-degron ***,this study sheds light on how sars-cov-2 ORF10 exploits the ubiquitination machinery for proteasomal degradation,and offers valuable insights for optimizing PROTAC-based drug design based on NTH CUL2ZYG11B interaction,while pinpointing a promising target for the development of treatments for covID-19.

关键词： sars-cov-2 ORF10 Crystal structure cullin-2 RING E3 ligase Drug design

Structural elucidation of sars-cov-2 vital proteins: Computational methods reveal potential drug candidates against main protease, Nsp12 polymerase and Nsp13 helicase

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Journal of Pharmaceutical Analysis 2020年第4期10卷 320-328页

作者： Muhammad Usman Mirza Matheus Froeyen Department of Pharmaceutical and Pharmacological Sciences Rega Institute for Medical ResearchMedicinal ChemistryUniversity of LeuvenB-3000LeuvenBelgium

Recently emerged sars-cov-2 caused a major outbreak of coronavirus disease 2019(covID-19)and instigated a widespread fear,threatening global health *** date,no licensed antiviral drugs or vaccines are available against covID-19 although several clinical trials are under way to test possible *** this urgent situation,computational drug discovery methods provide an alternative to tiresome high-throughput screening,particularly in the hit-to-lead-optimization *** of small molecules that specifically target viral replication apparatus has indicated the highest potential towards antiviral drug *** this work,we present potential compounds that specifically target sars-cov-2 vital proteins,including the main protease,Nsp12 RNA polymerase and Nsp13 *** integrative virtual screening and molecular dynamics simulations approach has facilitated the identification of potential binding modes and favourable molecular interaction profile of corresponding ***,the identification of structurally important binding site residues in conserved motifs located inside the active site highlights relative importance of ligand binding based on residual energy decomposition *** the current study lacks experimental validation,the structural information obtained from this computational study has paved way for the design of targeted inhibitors to combat covID-19 outbreak.

关键词： sars-cov-2 covID-19 outbreak cov-Mpro cov-Nsp12 polymerase cov-Nsp13 helicase