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m^(6)A modification of plant virus enables host recognition by NMD factors in plants

Science China(Life Sciences) 2024年第1期67卷 161-174页

作者： Hao He Linhao Ge Yalin Chen Siwen Zhao Zhaolei Li Xueping Zhou Fangfang Li State Key Laboratory for Biology of Plant Diseases and Insect Pests Institute of Plant ProtectionChinese Academy of Agricultural SciencesBeijing 100193China State Key Laboratory of Rice Biology Institute of BiotechnologyZhejiang UniversityHangzhou 310029China

N^(6)-methyladenosine(m^(6)A)is the most abundant eukaryotic mRNA modification and is involved in various biological processes.Increasing evidence has implicated that m^(6)Amodification is an important anti-viral defense mechanism in mammals and plants,but it is largely unknown how m^(6)Aregulates viral infection in plants.Here we report the dynamic changes and functional anatomy of m^(6)Ain Nicotiana benthamiana and Solanum lycopersicum during Pepino mosaic virus(PepMV)infection.m^(6)Amodification in the PepMV RNA genome is conserved in these two species.Overexpression of the m^(6)Awriters,mRNA adenosine methylase A(MTA),and HAKAI inhibit the PepMV RNA accumulation accompanied by increased viral m^(6)Amodifications,whereas deficiency of these writers decreases the viral RNA m^(6)Alevels but enhances virus infection.Further study reveals that the cytoplasmic YTH-domain family protein NbECT2A/2B/2C as m^(6)Areaders are involved in anti-viral immunity.Protein-protein interactions indicate that NbECT2A/2B/2C interact with nonsense-mediated mRNA decay(NMD)-related proteins,including NbUPF3 and NbSMG7,but not with NbUPF1.m^(6)Amodification-mediated restriction to PepMV infection is dependent on NMD-related factors.These findings provide new insights into the functionality of m^(6)Aanti-viral activity and reveal a distinct immune response that NMD factors recognize the m^(6)Areaders-viral m^(6)ARNA complex for viral RNA degradation to limit virus infection in plants.

关键词： m^(6)A Pepino mosaic virus plant defense m^(6)A readers NMD factors

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The RNA m^(6)A demethylase ALKBH5 drives emergency granulopoiesis and neutrophil mobilization by upregulating G-CSFR expression

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Cellular & Molecular Immunology 2024年第1期21卷 6-18页

作者： Yang Liu Renjie Song Zhike Lu Lu Zhao Xinyi Zhan Yini Li Xuetao Cao Department of Immunology Center for ImmunotherapyInstitute of Basic Medical SciencesPeking Union Medical CollegeChinese Academy of Medical SciencesBeijingChina Suzhou institute of Systems Medicine Chinese Academy of Medical SciencesSuzhouChina Frontier Research Center for Cell Response Institute of ImmunologyCollege of Life SciencesNankai UniversityTianjinChina School of Life Sciences Westlake UniversityHangzhouChina

Emergency granulopoiesis and neutrophil mobilization that can be triggered by granulocyte colony-stimulating factor(G-CSF)through its receptor G-CSFR are essential for antibacterial innate defense.However,the epigenetic modifiers crucial for intrinsically regulating G-CSFR expression and the antibacterial response of neutrophils remain largely unclear.N6-methyladenosine(m^(6)A)RNA modification and the related demethylase alkB homolog 5(ALKBH5)are key epigenetic regulators of immunity and inflammation,but their roles in neutrophil production and mobilization are still unknown.We used cecal ligation and puncture(CLP)-induced polymicrobial sepsis to model systemic bacterial infection,and we report that ALKBH5 is required for emergency granulopoiesis and neutrophil mobilization.ALKBH5 depletion significantly impaired the production of immature neutrophils in the bone marrow of septic mice.In addition,Alkbh5-deficient septic mice exhibited higher retention of mature neutrophils in the bone marrow and defective neutrophil release into the circulation,which led to fewer neutrophils at the infection site than in their wild-type littermates.During bacterial infection,ALKBH5 imprinted production-and mobilization-promoting transcriptome signatures in both mouse and human neutrophils.Mechanistically,ALKBH5 erased m^(6)A methylation on the CSF3R mRNA to increase the mRNA stability and protein expression of G-CSFR,consequently upregulating cell surface G-CSFR expression and downstream STAT3 signaling in neutrophils.The RIP-qPCR results confirmed the direct binding of ALKBH5 to the CSF3R mRNA,and the binding strength declined upon bacterial infection,accounting for the decrease in G-CSFR expression on bacteria-infected neutrophils.Considering these results collectively,we define a new role of ALKBH5 in intrinsically driving neutrophil production and mobilization through m^(6)A demethylation-dependent posttranscriptional regulation,indicating that m^(6)A RNA modification in neutrophils is a potential target for treating bacteria

关键词： Emergency granulopoiesis Neutrophil mobilization ALKBH5 m^(6)A RNA modification G-CSF receptor

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Medullary thymic epithelial cells,the indispensable player in central tolerance

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Science China(Life Sciences) 2013年第5期56卷 392-398页

作者： SHI YaoYao ZHU MingZhao Key Laboratory of infection and immunity Institute of BiophysicsChinese Academy of Sciences University of Chinese Academy of Sciences

Crosstalk between thymocytes and thymic epithelial cells is critical for T cell development and the establishment of central tolerance.Medullary thymic epithelial cells(mTECs) play important roles in the late stage of T cell development,especially negative selection and Treg generation.The function of mTECs is highly dependent on their characteristic features such as ectopic expression of peripheral tissue restricted antigens(TRAs) and their master regulator-autoimmune regulator(Aire),expression of various chemokines and cytokines.In this review,we summarize the current understanding of cellular and molecular mechanisms of mTEC development and its functions in T cell development and the establishment of central tolerance.The open questions in this field are also discussed.Understanding the function and underlying mechanisms of mTECs will contribute to the better control of autoimmune diseases and the improvement of immune reconstitution during aging or after infection,chemotherapy or radiotherapy.

关键词：胸腺上皮细胞髓质中央 T细胞发育免疫性疾病球员调节性T细胞分子机制

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RelB intrinsically regulates the development and function of medullary thymic epithelial cells

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Science China(Life Sciences) 2018年第9期61卷 1039-1048页

作者： Caiwei Jin Mingzhao Zhu Key Laboratory of infection and immunity Institute of Biophysics Chinese Academy of Sciences College of Life Sciences University of Chinese Academy of Sciences

Medullary thymic epithelial cells(mTECs) act as one of the major stromal components in the thymus for selection and maturation of both conventional T cells and non-conventional T cells. Extensive efforts have been spent to understand how mTEC development and function are regulated. Although RelB has been well accepted to be a critical transcriptional factor for mTEC development, the underlying mechanisms still remain largely unclear. In this study, by generating thymic epithelial cell specific RelB deficient mice, we found that epithelial intrinsic RelB is required for mTEC homeostatic proliferation. Mechanistically, RelB regulates the expression of genes involved in cell cycle. Functionally, lack of intrinsic RelB in thymic epithelial cells results in dramatically reduced population of mTECs and impaired development of thymic invariant natural killer T(iNKT) cells and intraepithelial lymphocyte precursors(IELPs). This study thus reveals an epithelial intrinsic role of RelB on mTEC development and function.

关键词：房间上皮开发调整和函数淋巴细胞机械学

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A human monoclonal antibody neutralizes SARS-CoV-2 Omicron variants bytargeting the upstream region of spike protein HR2 motif

hLife

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hLife 2024年第3期2卷 126-140页

作者： Hang Su Jun Zhang Zhenfei Yi Sajid Khan Mian Peng Liang Ye Alan Bao Han Zhang Guangli Suo Qian Li Housheng Zheng Dandan Wu Thomas J.Kipps Lanfeng Wang Zhenghong Lin Suping Zhang Shenzhen Key Laboratory of Precision Medicine for Hematological Malignancies Guangdong Key Laboratory for Genome Stability andHuman Disease PreventionDepartment of PharmacologySchool of Basic Medical SciencesBase for International Science and TechnologyCooperation:Carson Cancer Stem Cell Vaccines R&D CenterInternational Cancer CenterShenzhen University Medical SchoolShenzhenUniversityGuangdongChina School of Life Sciences Chongqing UniversityChongqingChina The Center for Microbes Development and HealthCAS Key Laboratory of Molecular Virology&ImmunologyShanghai Institute of Immunityand InfectionChinese Academy of SciencesUniversity of Chinese Academy of SciencesShanghaiChina College of Life Sciences University of Chinese Academy of SciencesBeijingChina Department of Critical Care Medicine Shenzhen Luohu People’s HospitalGuangdongChina University of California BerkeleyCaliforniaUSA Xenta Biomedical Science Co. LtdGuangdongChina CAS Key Laboratory of Nano-Bio Interface Suzhou Institute of Nano-Tech and Nano-BionicsChinese Academy of SciencesJiangsuChina Center of Novel Therapeutics University of CaliforniaSan DiegoCaliforniaUSA

The continuous emergence of new severe acute respiratory syndrome coronavirus 2(SARS-CoV-2)variants meansthere is a need to explore additional strategies to develop broad-spectrum vaccines or therapeutics for individuals remaining at risk of coronavirus disease 2019(COVID-19).Neutralizing monoclonal antibody(mAb)that binds to theconserved S2 subunit of the SARS-CoV-2 spike(S)protein alone,or in combination with mAb that binds to the receptor-binding domain(RBD)of S protein,might be effective in eliciting protection from infection by a variety of SARS-CoV2 variants.Using high-throughput single-cell immunoglobulin sequencing of B cells from COVID-19-convalescent donors,we identified a high-affinity S2-specific mAb-39,that could inhibit original SARS-CoV-2 strain,Omicron BA.1,BA.2.86,BA.4,BA.5,and EG.5.1 S protein-mediated membrane fusion,leading to the neutralization of these pseudoviralinfections.Moreover,mAb-39 could also improve the neutralizing activity of anti-RBD antibody against the highlyneutralization-resistant Omicron variants.Molecular docking and point mutation analyses revealed that mAb-39 recognized epitopes within the conserved upstream region of the heptad repeat 2(HR2)motif of the S2 subunit.Collectively,these findings demonstrate that targeting the conserved upstream region of the HR2 motif(e.g.,using mAbs)provides anovel strategy for preventing the infection of SARS-CoV-2 and its variants.

关键词： coronavirus disease 2019(COVID-19) severe acute respiratory syndrome coronavirus 2(SARS-CoV-2)Omicron variants monoclonal antibody upstream region of heptad repeat 2(HR2) immunoglobulin repertoiresequencing

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Associations of PNPLA3 and LEP genetic polymorphisms with metabolic-associated fatty liver disease in Thai people living with human immunodeficiency virus

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World Journal of Hepatology 2024年第3期16卷 366-378页

作者： Kanuengnit Choochuay Punna Kunhapan Apichaya Puangpetch Sissades Tongsima Pornpen Srisawasdi Abhasnee Sobhonslidsuk Somnuek Sungkanuparph Mohitosh Biswas Chonlaphat Sukasem Program in Translational Medicine Faculty of Medicine Ramathibodi HospitalMahidol UniversityBangkok 10400Thailand School of Pharmacy Walailak UniversityNakhon Si Thammarat 80161Thailand Laboratory for Pharmacogenomics Division of Pharmacogenomics and Personalized MedicineSomdech Phra Debaratana Medical CenterDepartment of PathologyFaculty of Medicine Ramathibodi HospitalMahidol UniversityBangkok 10400Thailand Department of Medical Sciences Ministry of Public HealthNonthaburi 11000Thailand National Biobank of Thailand National Center for Genetic Engineering and BiotechnologyPathum Thani 12120Thailand Division of Clinical Chemistry Department of PathologyFaculty of Medicine Ramathibodi HospitalMahidol UniversityBangkok 10400Thailand Division of Gastroenterology and Hepatology Department of MedicineFaculty of Medicine Ramathibodi HospitalMahidol UniversityBangkok 10400Thailand Chakri Naruebodindra Medical institute Faculty of Medicine Ramathibodi HospitalMahidol UniversitySamut Prakan 10540Thailand Department of Pharmacy University of RajshahiRajshahi 6205Bangladesh Pharmacogenomics Clinic Bumrungrad Genomic Medicine InstituteBumrungrad International HospitalBangkok 10110Thailand Research and Development Laboratory Bumrungrad International HospitalBangkok 10110Thailand MRC Centre for Drug Safety Science Department of Pharmacology and TherapeuticsInstitute of SystemsMolecular and Integrative BiologyUniversity of Liverpool Liverpool L693GLUnited Kingdom Faculty of Pharmaceutical Sciences Burapha UniversityChonburi 20131Thailand

BACKGROUND The prevalence of metabolic-associated fatty liver disease(MAFLD)is a growing public health issue in people living with human immunodeficiency virus(PLWH).However,the pathophysiology of MAFLD is still unknown,and the role of genetic variables is only now becoming evident.AIM To evaluate the associations of gene-polymorphism-related MAFLD in PLWH.METHODS The study employed transient elastography with a controlled attenuation parameter≥248 dB/m to identify MAFLD in patients from a Super Tertiary Hospital in central Thailand.Candidate single-nucleotide polymorphisms(SNPs)were genotyped using TaqMan®MGB probe 5'nuclease assays for seven MAFLD-related genes.Statistical analyses included SNP frequency analysis,Fisher's Exact and Chi-square tests,odds ratio calculations,and multivariable logistic regression.RESULTS The G-allele carriers of PNPLA3(rs738409)exhibited a two-fold rise in MAFLD,increasing by 2.5 times in MAFLD with human immunodeficiency virus infection.The clinical features and genetic patterns imply that LEP rs7799039 A-allele carriers had a nine times(P=0.001)more significant chance of developing aberrant triglyceride among PLWH.CONCLUSION The current study shows an association between PNPLA3 rs738409 and LEP rs7799039 with MAFLD in PLWH.

关键词： PNPLA3 LEP Metabolic-associated fatty liver disease People living with HIV Thai

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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 immunity.Knowledge about this interplay can not only help us identify biological mechanisms but also reveal pathogen vulnerabilities that can be leveraged therapeutically.The 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 attention.Here,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 systems.We 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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Mpox (monkeypox) knowledge, concern, willingness to change behaviour, and seek vaccination: Results of a national cross-sectional survey

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Sexual Health 2023年第5期20卷 403-410页

作者： Macgibbon J. Cornelisse V.J. Smith A.K.J. Broady T.R. Hammoud M.A. Bavinton B.R. Heath-Paynter D. Vaughan M. Wright E.J. Holt M. Centre for Social Research in Health UNSW Sydney Sydney NSW Australia Kirby institute UNSW Sydney Sydney NSW Australia NSW Health Sydney NSW Australia Health Equity Matters Sydney NSW Australia ACON Sydney NSW Australia Department of Infectious Diseases Alfred Hospital and Central Clinical School Monash University Melbourne VIC Australia Burnet institute Melbourne VIC Australia The Peter Doherty institute of infection and immunity Melbourne VIC Australia

Background: In mid-2022, a global mpox (formerly 'monkeypox') outbreak affecting predominantly gay and bisexual men emerged in non-endemic countries. Australia had never previously recorded mpox cases and there was no prior research on knowledge or attitudes to mpox among gay and bisexual men across Australia. Methods: We conducted a national, online cross-sectional survey between August 2022 and September 2022. Participants were recruited through community organisation promotions, online advertising, and direct email invitations. Eligible participants were gay, bisexual or queer; identified as male (cisgender or transgender) or non-binary; aged 16 years or older; and lived in Australia. The main outcome measures were: knowledge and concern about mpox; recognition of mpox symptoms and transmission routes; vaccination history; acceptability of behavioural changes to reduce mpox risk, and willingness to be vaccinated. Results: Of 2287 participants, most participants were male (2189/2287; 95.7%) and gay (1894/2287; 82.8%). Nearly all had heard about mpox (2255/2287; 98.6%), and the majority were concerned about acquiring it (1461/2287; 64.4%). Most of the 2268 participants not previously diagnosed with mpox correctly identified skin lesions (2087; 92%), rash (1977; 87.2%), and fever (1647; 72.6%) as potential symptoms, and prolonged and brief skin-To-skin contact as potential ways to acquire mpox (2124, 93.7%; and 1860, 82%, respectively). The most acceptable behavioural changes were reducing or avoiding attendance at sex parties (1494; 65.9%) and sex-on-premises venues (1503; 66.4%), and having fewer sexual partners (1466; 64.6%). Most unvaccinated and undiagnosed participants were willing to be vaccinated (1457/1733; 84.1%). Conclusions: People at risk of mpox should be supported to adopt acceptable risk reduction strategies during outbreaks and to seek vaccination. © 2023 CSIRO. All rights reserved.

关键词： attitudes Australia gay and bisexual men men who have sex with men monkeypox mpox sexual behaviour sexual practice sexually transmissible infection vaccination vaccine

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Mechanisms and strategies to overcome immunotherapy resistance in hepatobiliary malignancies

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Hepatobiliary & Pancreatic Diseases international 2022年第5期21卷 430-439页

作者： Jia Xiong Qing-Qing Wang institute of Immunology Zhejiang University School of MedicineHangzhou 310058China The Key Laboratory for immunity and Inflammatory Diseases of Zhejiang Province Hangzhou 310058China

Unprecedented advances have been achieved in hepatobiliary cancer treatment with immune checkpoint blockade(ICB).However,the efflcacy of ICB in patients with hepatobiliary malignancies is still limited.Resistance to immunotherapies is often orchestrated by complicated tumor-host-microenvironment interactions but could also occur after initial efflcacy,mostly when only partial responses are obtained.Clarification of cancer-resistance mechanisms will be beneficial to provide the rationale for the administration of personalized drugs.Here,we review the factors related to resistance to immune-targeted therapies in hepatobiliary malignancies and discuss the potential strategies for overcoming resistance and future directions of immunotherapy development.

关键词： Cancer immunotherapy Hepatobiliary malignancies Immune checkpoint blockade Drug resistance

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Paneth cells: the hub for sensing and regulating intestinal flora

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Science China(Life Sciences) 2016年第5期59卷 463-467页

作者： Zheng Zhang Zhihua Liu Department of Gastroenterology the Affiliated Yixing Hospital of Jiangsu University CAS Key Laboratory of infection and immunity Institute of Biophysics Chinese Academy of Sciences

The complex interplay between symbiotic bacteria and host immunity plays a key role in shaping intestinal homeostasis and maintaining host health. Paneth cells, as one of the major producers of antimicrobial peptides in the intestine under steady-state conditions, play a vital role in regulating intestinal flora. Many studies on inflammatory bowel disease(IBD)-associated genes have put Paneth cells at the center of IBD pathogenesis. In this perspective, we focus on mechanistic studies of different cellular processes in Paneth cells that are regulated by various IBD-associated susceptibility genes, and we discuss the hypothesis that Paneth cells function as the central hub for sensing and regulating intestinal flora in the maintenance of intestinal homeostasis.

关键词：细胞分子机理肠道菌群感知宿主免疫肠道内环境 IBD 相互作用共生细菌

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