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Early-life EV-A71 infection augments allergen-induced airway inflammation in asthma through trained macrophage immunity

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Cellular & Molecular Immunology 2021年第2期18卷 472-483页

作者： Pei-Chi Chen Yu-Ting Shao Miao-Hsi Hsieh Hui-Fang Kao Wen-Shuo Kuo Shih-Min Wang Shun-Hua Chen Lawrence Shih Hsin Wu Hui-Ju Tsai Jiu-Yao Wang Institute of Basic Medical Sciences College of MedicineNational Cheng Kung UniversityTainanTaiwanChina Department of Microbiology and Immunology College of MedicineNational Cheng Kung UniversityTainanTaiwanChina Center for Allergy and Clinical Immunology Research College of MedicineNational Cheng Kung UniversityTainanTaiwanChina Department of Nursing National Tainan Junior College of NursingTainanTaiwanChina School of Chemistry and Materials Science Nanjing University of Information Science and TechnologyNanjingChina Department of Pediatrics National Cheng Kung University HospitalTainanTaiwanChina Graduate Institute of Biomedical Sciences China Medical UniversityTaichungTaiwanChina Division of Biostatistics and Bioinformatics Institute of Population Health SciencesNational Health Research InstitutesZhunanTaiwanChina Department of Pediatrics National Cheng Kung University HospitalNo139Sheng-Li RoadTainan 70428 TaiwanChina

Virus-induced asthma is prevalent among children,but its underlying mechanisms are unclear.Accumulated evidence indicates that early-life respiratory virus infection increases susceptibility to allergic asthma.Nonetheless,the relationship between systemic virus infections,such as enterovirus infection,and the ensuing effects on allergic asthma development is unknown.Early-life enterovirus infection was correlated with higher risks of allergic diseases in children.Adult mice exhibited exacerbated mite allergen-induced airway inflammation following recovery from EV-A71 infection in the neonatal period.Bone marrow-derived macrophages(BMDMs)from recovered EV-A71-infected mice showed sustained innate immune memory(Trained immunity)that could drive naïve T helper cells toward Th2 and Th17 cell differentiation when in contact with mites.Adoptive transfer of EV-A71-trained BMDMs induced augmented allergic inflammation in naïve recipient mice,which was inhibited by 2-deoxy-D-glucose(2-DG)pretreatment,suggesting that trained macrophages following enterovirus infection are crucial in the progression of allergic asthma later in life.

关键词： Trained immunity allergy asthma

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EZH2 identifies the precursors of human natural killer cells with Trained immunity

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Cancer Biology & Medicine 2021年第4期18卷 1021-1039页

作者： Chen Zhang Jie Yin Jian Zheng Jun Xiao Jiajian Hu Yudong Su Kaichen Zhou Yingchi Zhang Xuzhen Zhang Hong Zhang Qian Sun Yang Wang Wenwen Yu Feng Wei Qiang Zhao Long Li Xiubao Ren Department of Immunology and Biotherapy Key Laboratory of Cancer Immunology and BiotherapyTianjin Medical University Cancer Institute and HospitalNational Clinical Research Center for CancerKey Laboratory of Cancer Prevention and TherapyTianjinTianjin’s Clinical Research Center for CancerTianjin 300060China Department of Immunology Key Laboratory of Immune Microenvironment and Disease of the Ministry of EducationTianjin Medical UniversityTianjin 300070China Department of Pediatric Cancer Tianjin Medical University Cancer Institute and HospitalTianjin 300060China State Key Laboratory of Experimental Hematology and Division of Pediatric Blood Diseases Center Institute of Hematology and Blood Diseases HospitalChinese Academy of Medical Sciences and Peking Union Medical CollegeTianjin 300000China Center for Stem Cell Medicine Chinese Academy of Medical SciencesBeijing 100730China Research Center of Basic Medicine Science Tianjin Medical UniversityTianjin 300070China

Objective:Trained immunity of natural killer(NK)cells has shown great potential in the treatment of cancers by eliciting enhanced effector responses to restimulation by cytokines or cancer cells for long time periods after preactivation.However,the human NK cells responsible for the generation and maintenance of Trained immunity are largely unknown.We hypothesized that heterogeneous human NK cells would respond differentially to stimulation with a combination of IL-12,IL-15,and IL-18,and that an NK cell subset might exist that is mainly responsible for the induction of Trained immunity.On the basis of our hypothesis,we aimed to identify the subset from which cytokine-trained human NK cells originate and to explore possible regulatory targets for drug intervention.Methods:Flow cytometry assays were performed to analyze the functions of cytokine-trained NK cells and examine cell division and protein expression in NK cell subsets.Single-cell RNA sequencing(scRNA-seq)plus TotalSeq™technology was used to track the heterogeneity of NK cells during the induction of Trained immunity.Results:Traditional developmental markers for peripheral NK cells were unable to identify the precursors of human NK cells with Trained immunity.Therefore,we used scRNA-seq plus TotalSeq™technology to track the heterogeneity of NK cells during the induction of Trained immunity and identified a unique cluster of CD57−NKG2A+EZH2+IFNG+MKI67+IL12R+IL15R+IL18R+NK cells.Enrichment and pseudotime trajectory analyses suggested that this cluster of NK cells contained the precursor of trained NK cells.We then used flow cytometry to further investigate the role of EZH2 in trained NK precursors and found that CD57−NKG2A+EZH2+NK cells had faster cell cycles and an enhanced trained phenotype,and EZH2 inhibition significantly impaired the induction of Trained immunity in NK cells.These results suggested that EZH2 is a unique epigenetic marker of precursors of human NK cells with Trained immunity.Conclusions:Our work revealed human NK heterogeneity in the in

关键词： Natural killer cells Trained immunity precursor EZH2 cell cycle

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Detection of Trained immunity in rabbits with coccidia infection

Detection of trained immunity in rabbits with coccidia infec...

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第十一届全国寄生虫学青年工作者学术研讨会

作者： Jingchuan Zhong Chao Li Qin Liao Chunxia Lu Xianyong Liu Xun Suo National Animal Protozoal Laboratory & College of Veterinary Medicine China Agricultural University

Recent studies showed that Trained immunity,or innate immune memory,demonstrates adaptive characteristics after challenge with pathogens or their products.This new concept leads us to hypothesis that Trained immunity plays important role in the protection of rabbits against re-infection with Eimeria,which are the causative agents of rabbit coccidiosis threating the rabbit industry.To test whether Eimeria could stimulate Trained immunity in rabbits against homologous and heterologous challenge,two groups of rabbits were individually immunized with 104 E.intestinalis oocysts,then challenged either with 106 E.intestinalis or 106 E.magna oocysts 14 days post immunization.Heparinized blood was sampled each day from day 0 to 9 post immunization(pi) and post challenge(pc).Numbers of white blood cells(WBC),polymorphonuclear neutrophils(PMN) and lymphocytes(LYM) were analyzed.For immunized groups,the numbers of WBC,PMN and LYM increased,and the peak numbers occurred on day 7 to 8 pi with a 2-fold and 1.8-fold higher than those on day 0 pi,respectively.After homologous or heterologous challenge,both WBC and PMN numbers in immunized groups increased with the peak numbers occurred on day 2 and 3 post challenge,respectively;while the LYM numbers increased from day 6 post challenge.Together,the results suggest that immunization with E.intestinalis could induce Trained immunity against homologous and heterologous challenge.

关键词： Trained immunity Rabbit Eimeria intestinalis Eimeria magna

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Bacillus Calmette Guerin induces Trained immunity in murine BMDMs

Bacillus Calmette Guerin induces trained immunity in murine ...

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第十一届全国免疫学学术大会

作者： Peng Zhangli Yue yan Xiong sidong Soochow University

Background:Bacille Calmette-Guerin(BCG),the vaccine used for the prevention of tuberculosis(TB) has continuously been in use for more than 90 years.In addition to its protection effect against TB,BCG has attracted more and more attention and interests because of its potent non-specific immune-enhancing ability.It has been showed that BCG could obviously enhance host innate immune responses against tumors,impact severity and prognosis of many allergic,and many auto-immune diseases.This "memory-like" phenomenon of innate immune responses was termed as "Trained immunity".So far experiments of BCG-induced Trained immunity are mainly performed on monocytes.Considering that monocytes could further enter peripheral tissues,differentiate into macrophages,which are responsible for the activation and modulation of subsequent immune responses.So it is important to explore whether BCG could induces Trained immunity in macrophages or not.Objective:To investigate whether macrophages can be trained by BCG or not.Methods:BMDMs were primed with different doses of BCG for 24 h,and then washed to remove all stimuli.After resting for 5 days,cells were stimulated with LPS.The levels of proinflammatory cytokines were determined by enzymelinked immunosorbent assays(ELISA).Results:Compared with BMDMs without BCG priming,cells priming with BCG produced significantly higher levels of proinflammatory cytokines(TNF-α and IL-6).The level of TNF-α in BMDMs without BCG priming was 530 pg/ml,while with BCG priming,the level of TNF-α could significantly increased to 1200 pg/ml.Similar phenomenon was alsoobserved in IL-6,in which was 800 pg/ml in BMDMs without BCG priming,but increased to 1400 pg/ml with BCG priming.Conclusion:BCG could efficiently induce Trained immunity in the differentiated macrophages(BMDMs),our data further extend of the ‘‘Trained immunity’’ phenomenon from monocytes to macrophages and this might help the design of further vaccination.

关键词： Bacille Calmette-Guerin macrophages Trained immunity

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Prenatal programing of motivated behaviors:can innate immunity prime behavior?

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Neural Regeneration Research 2023年第2期18卷 280-283页

作者： Larisa Montalvo-Martínez Gabriela Cruz-Carrillo Roger Maldonado-Ruiz Luis ATrujillo-Villarreal Eduardo AGarza-Villarreal Alberto Camacho-Morales Universidad Autónoma de Nuevo León Department of BiochemistryCollege of MedicineMonterreyMéxico Universidad Autónoma de Nuevo León Neurometabolism UnitCenter for Research and Development in Health SciencesMonterreyMéxico Universidad Nacional Autónoma de México Campus Juriquilla Instituto de NeurobiologíaQueretaroMéxico

Prenatal programming during pregnancy sets physiological outcomes in the offspring by integrating external or internal stimuli.Accordingly,pregnancy is an important stage of physiological adaptations to the environment where the fetus becomes exposed and adapted to the maternal milieu.Maternal exposure to high-energy dense diets can affect motivated behavior in the offs p ring leading to addiction and impaired sociability.A high-energy dense exposure also increases the pro-inflammatory cytokines profile in plasma and brain and favors microglia activation in the offspring.While still under investigation,prenatal exposure to high-energy dense diets promotes structural abnormalities in selective brain regions regulating motivation and social behavior in the offspring.The current review addresses the role of energy-dense foods programming central and peripheral inflammatory profiles during embryonic development and its effect on motivated behavior in the offspring.We provide preclinical and clinical evidence that supports the contribution of prenatal programming in shaping immune profiles that favor structural and brain circuit disruption leading to aberrant motivated behaviors after birth.We hope this minireview encourages future research on novel insights into the mechanisms underlying maternal programming of motivated behavior by central immune networks.

关键词： addiction autism behavior cytokines diet maternal immune activation prenatal programming sociability Trained immunity western-diets

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Effects of Bacillus Calmette-Guerin on immunometabolism,microbiome and liver diseases

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Liver Research 2023年第2期7卷 116-123页

作者： Muhammad Umair Ijaz Farzam Vaziri Yu-Jui Yvonne Wan Department of Medical Pathology and Laboratory Medicine University of California Davis School of MedicineSacramentoCAUSA

Metabolic diseases have overtaken infectious diseases as the most serious public health issue and economic burden in most countries.Moreover,metabolic diseases increase the risk of having infectious diseases.The treatment of metabolic disease may require a long-term strategy of taking multiple medications,which can be costly and have side effects.Attempts to expand the therapeutic use of vaccination to prevent or treat metabolic diseases have attracted significant interest.A growing body of evidence indicates that Bacillus Calmette-Guerin(BCG)offers protection against non-infectious diseases.The non-specific effects of BCG occur likely due to the induction of Trained immunity.In this regard,understanding how BCG influences the development of chronic metabolic health including liver diseases would be important.This review focuses on research on BCG,the constellation of disorders associated with metabolic health issues including liver diseases and diabetes as well as how BCG affects the gut microbiome,immunity,and metabolism.

关键词： Bacillus Calmette-Guerin(BCG) Liver disease Vaccination Gut microbiota Metabolic diseases Trained immunity Diabetes

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Human immunology and immunotherapy:main achievements and challenges

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Cellular & Molecular Immunology 2021年第4期18卷 805-828页

作者： Jezabel Varade Susana Magadan Africa Gonzalez-Fernandez ONBIO Centro de Investigaciones BiomedicasUniversidade de VigoImmunology GroupCampus Universitario LagoasMarcosende36310 VigoSpain Instituto de Investigacidn Sanitaria Galicia Sur(IIS-Galicia Sur) ERGAS-UVIGOVigoSpain

The immune system is a fascinating world of cells,soluble factors,interacting cells,and tissues,all of which are interconnected.The highly complex nature of the immune system makes it difficult to view it as a whole,but researchers are now trying to put all the pieces of the puzzle together to obtain a more complete picture.The development of new specialized equipment and immunological techniques,genetic approaches,animal models,and a long list of monoclonal antibodies,among many other factors,are improving our knowledge of this sophisticated system.The different types of cell subsets,soluble factors,membrane molecules,and cell functionalities are some aspects that we are starting to understand,together with their roles in health,aging,and illness.This knowledge is filling many of the gaps,and in some cases,it has led to changes in our previous assumptions;e.g.,adaptive immune cells were previously thought to be unique memory cells until trained innate immunity was observed,and several innate immune cells with features similar to those of cytokine-secreting T cells have been discovered.Moreover,we have improved our knowledge not only regarding immune-mediated illnesses and how the immune system works and interacts with other systems and components(such as the microbiome)but also in terms of ways to manipulate this system through immunotherapy.The development of different types of immunotherapies,including vaccines(prophylactic and therapeutic),and the use of pathogens,m onodonal antibodies,recombinant proteins,cytokines,and cellular immunotherapies,are changing the way in which we approach many diseases,especially cancer.

关键词： Vaccines CAR T cells Trained immunity Microbiota Cancer Monoclonal antibodies

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Advances in immune response to pulmonary infection:Nonspecificity,specificity and memory

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Chronic Diseases and Translational Medicine 2023年第2期9卷 71-81页

作者： Jianqiao Xu Lixin Xie College of Pulmonary&Critical Care Medicine 8th Medical CenterChinese PLA General HospitalBeijingChina Medical School of Chinese PLA BeijingChina

The lung immune response consists of various cells involved in both innate and adaptive immune processes.Innate immunity participates in immune resistance in a nonspecific manner,whereas adaptive immunity effectively eliminates pathogens through specific recognition.It was previously believed that adaptive immune memory plays a leading role during secondary infections;however,innate immunity is also involved in immune memory.Trained immunity refers to the long-term functional reprogramming of innate immune cells caused by the first infection,which alters the immune response during the second challenge.Tissue resilience limits the tissue damage caused by infection by controlling excessive inflammation and promoting tissue repair.In this review,we summarize the impact of host immunity on the pathophysiological processes of pulmonary infections and discuss the latest progress in this regard.In addition to the factors influencing pathogenic microorganisms,we emphasize the importance of the host response.

关键词： adaptive immunity innate immunity lung infection Trained immunity

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