Brucellosis,caused by Brucella,is one of the most common zoonosis.However,there is still no vaccine for human use.Although some live attenuated vaccines have been approved for animals,the protection effect is not idea...Brucellosis,caused by Brucella,is one of the most common zoonosis.However,there is still no vaccine for human use.Although some live attenuated vaccines have been approved for animals,the protection effect is not ideal.In this study,we developed a dual-antigen nanoconjugate vaccine containing both polysaccharide and protein antigens against Brucella.First,the antigenic polysaccharide was covalently coupled to the outer membrane protein Omp19 using protein glycan coupling technology,and then it was successfully loaded on a nano-carrier through the SpyTag/SpyCatcher system.After confirming the efficient immune activation and safety performance of the dual-antigen nanoconjugate vaccine,the potent serum antibody response against the two antigens and remarkable protective effect in non-lethal and lethal Brucella infection models were further demonstrated through different routes of administration.These results indicated that the dual-antigen nanoconjugate vaccine enhanced both T helper 1 cell(Th1)and Th2 immune responses and protected mice from Brucella infection.Furthermore,we found that this protective effect was maintained for at least 18 weeks.To our knowledge,this is the first Brucella vaccine bearing diverse antigens,including a protein and polysaccharide,on a single nanoparticle.Thus,we also present an attractive technology for co-delivery of different types of antigens using a strategy applicable to other vaccines against infectious diseases.展开更多
随着测序技术的发展和全基因组序列的不断积累,全基因组关联研究(genome-wide association study,GWAS)在人类复杂疾病研究中取得了丰硕成果,10余年间发现了数以万计的疾病风险因子。同样,GWAS也为探索细菌表型的遗传机制提供了新的工...随着测序技术的发展和全基因组序列的不断积累,全基因组关联研究(genome-wide association study,GWAS)在人类复杂疾病研究中取得了丰硕成果,10余年间发现了数以万计的疾病风险因子。同样,GWAS也为探索细菌表型的遗传机制提供了新的工具。自2013年第一项细菌GWAS(bacterial GWAS,BGWAS)工作发表以来,目前已有10多项相关研究报道,分别揭示了细菌宿主适应性、耐药性及毒力等表型的遗传机制,极大加深了人们对细菌遗传、进化及传播等方面的认识。本文对目前BGWAS的研究方法、应用成果及存在的问题进行了总结,并对BGWAS的研究前景进行了展望,旨在为微生物学领域开展BGWAS研究提供参考。展开更多
Colorectal cancer(CRC)is the third leading cancer globally.Metagenomics has been widely used to analyze the association between the gut microbiota and CRC based on bacterial genus-or species-level comparisons,providin...Colorectal cancer(CRC)is the third leading cancer globally.Metagenomics has been widely used to analyze the association between the gut microbiota and CRC based on bacterial genus-or species-level comparisons,providing evidence of dysbiosis in CRC development.However,this kind of analysis is unable to provide strain-level information for understanding the individual role of a species in CRC.Here,we used culturomics to isolate CRC mucosal samples and selected 158 Escherichia coli strains to reveal their differences in both genomics and functions by means of phylogenetic analysis and inflammatory induction based on cell and animal experiments.Through genomic comparison,these strains were divided into five phylogroups.The representative strains of each phylogroup significantly induced different levels of cytokine secretion by human leukemic monocyte(THP-1 cell)-based Transwell and animal experiments.Further bioinformatic analysis revealed different profiles of single-nucleotide polymorphisms,genes,and metabolic pathways in the different phylogroups,which can improve the current understanding of the phenotypic differences between these strains.The strain differences revealed in both genomics and functions indicate that the microbiota’s function at the strain level should be investigated in order to understand the interacting mechanisms between hosts and gut bacteria.展开更多
Bubonic plague caused by Yersinia pestis is highly infectious and often fatal.Characterization of the host immune response and its subsequent suppression by Y.pestis is critical to understanding the pathogenesis of Y....Bubonic plague caused by Yersinia pestis is highly infectious and often fatal.Characterization of the host immune response and its subsequent suppression by Y.pestis is critical to understanding the pathogenesis of Y.pestis.Here,we utilized single-cell RNA sequencing to systematically profile the transcriptomes of immune cells in draining lymph nodes(d LNs)during the early stage of Y.pestis infection.Dendritic cells responded to Y.pestis within 2 h post-infection(hpi),followed by the activation of macrophages/monocytes(Mφs/Mons)and recruitment of polymorphonuclear neutrophils(PMNs)to d LNs at 24 hpi.Analysis of cell-to-cell communication suggests that PMNs may be recruited to lymph nodes following the secretion of CCL9 by Mφs/Mons stimulated through CCR1-CCL9 interaction.Significant functional suppression of all the three innate immune cell types occurred during the early stage of infection.In summary,we present a dynamic immune landscape,at single-cell resolution,of murine d LNs involved in the response to Y.pestis infection,which may facilitate the understanding of the plague pathogenesis of during the early stage of infection.展开更多
The gut microbiota plays a key role in obesity and related metabolic disorders, and multiple factors including diet, host genotype, and age regulate it. Many studies have examined the contribution of extrinsic factors...The gut microbiota plays a key role in obesity and related metabolic disorders, and multiple factors including diet, host genotype, and age regulate it. Many studies have examined the contribution of extrinsic factors to the regulation of the gut microbiota, but the importance of the host genetic constitution cannot be ignored. Interleukin 17A(IL-17A), a pro-inflammatory cytokine, is important in the defense against infection and diseases. Here, we investigated the association among IL-17, a high-fat diet(HFD), and the gut microbiota. Mice deficient in IL-17A were resistant to diet-induced obesity and related diseases. Compared with the Ⅱ-17^(-/-)mice, wild-type(WT) mice challenged with HFD showed obvious weight fluctuations, such as those seen in type 2 diabetes, and hematological changes similar to those associated with metabolic syndrome. However, housing WT mice and Ⅱ-17a^(-/-)mice together significantly alleviated these symptoms in the WT mice. A metagenomic analysis of the mouse feces indicated that the microbial community compositions of these two groups differed before HFD feeding. The HFD mediated shifts in the gut microbial compositions, which were associated with the mouse phenotypes.We also identified potentially beneficial and harmful species present during this period, and drew networks of the most abundant species. A functional analysis indicated pathway changes in the WT and Ⅱ-17a^(-/-)mice when fed the HFD. Collectively, these data underscore the importance of the host factor IL-17 A in shaping and regulating the gut microbiota, which conversely, influences the host health.展开更多
The gut microbiota is involved in host responses to high altitude.However,the dynamics of intestinal microecology and their association with altitude-related illness are poorly understood.Here,we used a rat model of h...The gut microbiota is involved in host responses to high altitude.However,the dynamics of intestinal microecology and their association with altitude-related illness are poorly understood.Here,we used a rat model of hypobaric hypoxia challenge to mimic plateau exposure and monitored the gut microbiome,short-chain fatty acids(SCFAs),and bile acids(BAs)over 28 d.We identified weight loss,polycythemia,and pathological cardiac hypertrophy in hypoxic rats,accompanied by a large compositional shift in the gut microbiota,which is mainly driven by the bacterial families of Prevotellaceae,Porphyromonadaceae,and Streptococcaceae.The aberrant gut microbiota was characterized by increased abundance of the Parabacteroides,Alistipes,and Lactococcus genera and a larger Bacteroides to Prevotella ratio.Trans-omics analyses showed that the gut microbiome was significantly correlated with the metabolic abnormalities of SCFAs and BAs in feces,suggesting an interaction network remodeling of the microbiome-metabolome after the hypobaric hypoxia challenge.Interestingly,the transplantation of fecal microbiota significantly increased the diversity of the gut microbiota,partially inhibited the increased abundance of the Bacteroides and Alistipes genera,restored the decrease of plasma propionate,and moderately ameliorated cardiac hypertrophy in hypoxic rats.Our results provide an insight into the longitudinal changes in intestinal microecology during the hypobaric hypoxia challenge.Abnormalities in the gut microbiota and microbial metabolites contribute to the development of high-altitude heart disease in rats.展开更多
Flea-borne transmission is a recent evolutionary adaptation that distinguishes the deadly Yersinia pestis from its progenitor Y.pseudotuberculosis,a mild pathogen transmitted via the food-borne route.Y.pestis synthesi...Flea-borne transmission is a recent evolutionary adaptation that distinguishes the deadly Yersinia pestis from its progenitor Y.pseudotuberculosis,a mild pathogen transmitted via the food-borne route.Y.pestis synthesizes biofilms in the flea gut,which is important for fleaborne transmission.Yersinia biofilms are bacterial colonies surrounded by extracellular matrix primarily containing a homopolymer of N-acetyl-D-glucosamine that are synthesized by a set of specific enzymes.Yersinia biofilm production is tightly regulated at both transcriptional and post-transcriptional levels.All the known structural genes responsible for biofilm production are harbored in both Y.pseudotuberculosis and Y.pestis,but Y.pestis has evolved changes in the regulation of biofilm development,thereby acquiring efficient arthropod-borne transmission.展开更多
The gut microbiome has attracted increasing attention over the past 15 years.Along with the fast-growing body of research literature and media reports,the public's opinions on the gut microbiome have begun to appe...The gut microbiome has attracted increasing attention over the past 15 years.Along with the fast-growing body of research literature and media reports,the public's opinions on the gut microbiome have begun to appear polarized.Some believe that the gut microbiome is at the core of human health and is related to every single disease.To the opposite,some people question the scientific basis of gut microbiome studies and criticize that many of them are farfetched;there is even a joke spreading in the biomedical research field—"keeping gut microbiome in mind,no mechanism is hard to find".展开更多
基金supported by the National Key Research and Development Program of China(2021YFC2102100)the National Natural Science Foundation of China(U20A20361,32271507,81930122,and 82171819)the Beijing Postdoctoral Research Foundation(2021-ZZ-035)。
文摘Brucellosis,caused by Brucella,is one of the most common zoonosis.However,there is still no vaccine for human use.Although some live attenuated vaccines have been approved for animals,the protection effect is not ideal.In this study,we developed a dual-antigen nanoconjugate vaccine containing both polysaccharide and protein antigens against Brucella.First,the antigenic polysaccharide was covalently coupled to the outer membrane protein Omp19 using protein glycan coupling technology,and then it was successfully loaded on a nano-carrier through the SpyTag/SpyCatcher system.After confirming the efficient immune activation and safety performance of the dual-antigen nanoconjugate vaccine,the potent serum antibody response against the two antigens and remarkable protective effect in non-lethal and lethal Brucella infection models were further demonstrated through different routes of administration.These results indicated that the dual-antigen nanoconjugate vaccine enhanced both T helper 1 cell(Th1)and Th2 immune responses and protected mice from Brucella infection.Furthermore,we found that this protective effect was maintained for at least 18 weeks.To our knowledge,this is the first Brucella vaccine bearing diverse antigens,including a protein and polysaccharide,on a single nanoparticle.Thus,we also present an attractive technology for co-delivery of different types of antigens using a strategy applicable to other vaccines against infectious diseases.
文摘随着测序技术的发展和全基因组序列的不断积累,全基因组关联研究(genome-wide association study,GWAS)在人类复杂疾病研究中取得了丰硕成果,10余年间发现了数以万计的疾病风险因子。同样,GWAS也为探索细菌表型的遗传机制提供了新的工具。自2013年第一项细菌GWAS(bacterial GWAS,BGWAS)工作发表以来,目前已有10多项相关研究报道,分别揭示了细菌宿主适应性、耐药性及毒力等表型的遗传机制,极大加深了人们对细菌遗传、进化及传播等方面的认识。本文对目前BGWAS的研究方法、应用成果及存在的问题进行了总结,并对BGWAS的研究前景进行了展望,旨在为微生物学领域开展BGWAS研究提供参考。
基金supported by the National Natural Science Foundation for Key Programs of China(81790632)the National Natural Science Foundation of China(31970863)the Innovation Leader Team Program of Guangzhou(201809010014)。
文摘Colorectal cancer(CRC)is the third leading cancer globally.Metagenomics has been widely used to analyze the association between the gut microbiota and CRC based on bacterial genus-or species-level comparisons,providing evidence of dysbiosis in CRC development.However,this kind of analysis is unable to provide strain-level information for understanding the individual role of a species in CRC.Here,we used culturomics to isolate CRC mucosal samples and selected 158 Escherichia coli strains to reveal their differences in both genomics and functions by means of phylogenetic analysis and inflammatory induction based on cell and animal experiments.Through genomic comparison,these strains were divided into five phylogroups.The representative strains of each phylogroup significantly induced different levels of cytokine secretion by human leukemic monocyte(THP-1 cell)-based Transwell and animal experiments.Further bioinformatic analysis revealed different profiles of single-nucleotide polymorphisms,genes,and metabolic pathways in the different phylogroups,which can improve the current understanding of the phenotypic differences between these strains.The strain differences revealed in both genomics and functions indicate that the microbiota’s function at the strain level should be investigated in order to understand the interacting mechanisms between hosts and gut bacteria.
文摘Bubonic plague caused by Yersinia pestis is highly infectious and often fatal.Characterization of the host immune response and its subsequent suppression by Y.pestis is critical to understanding the pathogenesis of Y.pestis.Here,we utilized single-cell RNA sequencing to systematically profile the transcriptomes of immune cells in draining lymph nodes(d LNs)during the early stage of Y.pestis infection.Dendritic cells responded to Y.pestis within 2 h post-infection(hpi),followed by the activation of macrophages/monocytes(Mφs/Mons)and recruitment of polymorphonuclear neutrophils(PMNs)to d LNs at 24 hpi.Analysis of cell-to-cell communication suggests that PMNs may be recruited to lymph nodes following the secretion of CCL9 by Mφs/Mons stimulated through CCR1-CCL9 interaction.Significant functional suppression of all the three innate immune cell types occurred during the early stage of infection.In summary,we present a dynamic immune landscape,at single-cell resolution,of murine d LNs involved in the response to Y.pestis infection,which may facilitate the understanding of the plague pathogenesis of during the early stage of infection.
基金supported by the National High Technology Research and Development Program (2015AA020702)
文摘The gut microbiota plays a key role in obesity and related metabolic disorders, and multiple factors including diet, host genotype, and age regulate it. Many studies have examined the contribution of extrinsic factors to the regulation of the gut microbiota, but the importance of the host genetic constitution cannot be ignored. Interleukin 17A(IL-17A), a pro-inflammatory cytokine, is important in the defense against infection and diseases. Here, we investigated the association among IL-17, a high-fat diet(HFD), and the gut microbiota. Mice deficient in IL-17A were resistant to diet-induced obesity and related diseases. Compared with the Ⅱ-17^(-/-)mice, wild-type(WT) mice challenged with HFD showed obvious weight fluctuations, such as those seen in type 2 diabetes, and hematological changes similar to those associated with metabolic syndrome. However, housing WT mice and Ⅱ-17a^(-/-)mice together significantly alleviated these symptoms in the WT mice. A metagenomic analysis of the mouse feces indicated that the microbial community compositions of these two groups differed before HFD feeding. The HFD mediated shifts in the gut microbial compositions, which were associated with the mouse phenotypes.We also identified potentially beneficial and harmful species present during this period, and drew networks of the most abundant species. A functional analysis indicated pathway changes in the WT and Ⅱ-17a^(-/-)mice when fed the HFD. Collectively, these data underscore the importance of the host factor IL-17 A in shaping and regulating the gut microbiota, which conversely, influences the host health.
基金supported by the National Natural Science Foundation of China(81790632,31970863,and 31970088)the National Key Technology Research and Development Program of the Ministry of Science and Technology of China(2020YFA0509600)。
文摘The gut microbiota is involved in host responses to high altitude.However,the dynamics of intestinal microecology and their association with altitude-related illness are poorly understood.Here,we used a rat model of hypobaric hypoxia challenge to mimic plateau exposure and monitored the gut microbiome,short-chain fatty acids(SCFAs),and bile acids(BAs)over 28 d.We identified weight loss,polycythemia,and pathological cardiac hypertrophy in hypoxic rats,accompanied by a large compositional shift in the gut microbiota,which is mainly driven by the bacterial families of Prevotellaceae,Porphyromonadaceae,and Streptococcaceae.The aberrant gut microbiota was characterized by increased abundance of the Parabacteroides,Alistipes,and Lactococcus genera and a larger Bacteroides to Prevotella ratio.Trans-omics analyses showed that the gut microbiome was significantly correlated with the metabolic abnormalities of SCFAs and BAs in feces,suggesting an interaction network remodeling of the microbiome-metabolome after the hypobaric hypoxia challenge.Interestingly,the transplantation of fecal microbiota significantly increased the diversity of the gut microbiota,partially inhibited the increased abundance of the Bacteroides and Alistipes genera,restored the decrease of plasma propionate,and moderately ameliorated cardiac hypertrophy in hypoxic rats.Our results provide an insight into the longitudinal changes in intestinal microecology during the hypobaric hypoxia challenge.Abnormalities in the gut microbiota and microbial metabolites contribute to the development of high-altitude heart disease in rats.
基金the National Natural Science Foundation of China(Grant Nos.30930001,30900823,and 30771179)the National Basic Research Program(973 Program)(Grant No.2009CB522600)。
文摘Flea-borne transmission is a recent evolutionary adaptation that distinguishes the deadly Yersinia pestis from its progenitor Y.pseudotuberculosis,a mild pathogen transmitted via the food-borne route.Y.pestis synthesizes biofilms in the flea gut,which is important for fleaborne transmission.Yersinia biofilms are bacterial colonies surrounded by extracellular matrix primarily containing a homopolymer of N-acetyl-D-glucosamine that are synthesized by a set of specific enzymes.Yersinia biofilm production is tightly regulated at both transcriptional and post-transcriptional levels.All the known structural genes responsible for biofilm production are harbored in both Y.pseudotuberculosis and Y.pestis,but Y.pestis has evolved changes in the regulation of biofilm development,thereby acquiring efficient arthropod-borne transmission.
基金This work was supported by National Key Research and Development Program of China(2018YFC2000500)the Strategic Priority Research Program of the Chinese Academy of Sciences(XDB29020000)+1 种基金the National Natural Science Foundation of China(31771481,91857101)the National Social Science Foundation of China(16CZX064).We thank Prof.Liping Zhao from Shanghai Jiao Tong University for insightful advice and the many researchers,clinicians and industry specialists who participated in the discussion and provided valuable suggestions.
文摘The gut microbiome has attracted increasing attention over the past 15 years.Along with the fast-growing body of research literature and media reports,the public's opinions on the gut microbiome have begun to appear polarized.Some believe that the gut microbiome is at the core of human health and is related to every single disease.To the opposite,some people question the scientific basis of gut microbiome studies and criticize that many of them are farfetched;there is even a joke spreading in the biomedical research field—"keeping gut microbiome in mind,no mechanism is hard to find".