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Monocyte Reconstitution and Gut Microbiota Composition after Hematopoietic Stem Cell Transplantation

Clinical hematology international 2020年第4期2卷 156-164页

作者： Sejal Morjaria Allen W Zhang Sohn Kim Jonathan U Peled Simone Becattini Eric R Littmann Eric G Pamer Michael C Abt Miguel-Angel Perales Infectious Disease Department of Medicine Memorial Sloan Kettering Cancer Center New York NY USA. Department of Medicine Weill Cornell Medical College New York NY USA. Department of Epidemiology and Biostatistics Memorial Sloan Kettering Cancer Center New York NY USA. Immunology Program and Infectious Disease Service Memorial Sloan-Kettering Cancer Center New York NY USA. Adult Bone Marrow Transplantation Service Department of Medicine Memorial Sloan Kettering Cancer Center New York NY USA. Lucielle Castori Center for Microbes Inflammation and Cancer Sloan Kettering Institute New York NY USA. Department of Microbiology Perelman School of Medicine University of Pennsylvania Philadelphia PA 19104 USA.

BACKGROUND:Monocytes are an essential cellular component of the innate immune system that support the host's effectiveness to combat a range of infectious pathogens. Hemopoietic cell transplantation (HCT) results in transient monocyte depletion, but the factors that regulate recovery of monocyte populations are not fully understood. In this study, we investigated whether the composition of the gastrointestinal microbiota is associated with the recovery of monocyte homeostasis after HCT. METHODS:We performed a single-center, prospective, pilot study of 18 recipients of either autologous or allogeneic HCT. Serial blood and stool samples were collected from each patient during their HCT hospitalization. Analysis of the gut microbiota was done using 16S rRNA gene sequencing, and flow cytometric analysis was used to characterize the phenotypic composition of monocyte populations. RESULTS:Dynamic fluctuations in monocyte reconstitution occurred after HCT, and large differences were observed in monocyte frequency among patients over time. Recovery of absolute monocyte counts and subsets showed significant variability across the heterogeneous transplant types and conditioning intensities; no relationship to the microbiota composition was observed in this small cohort. CONCLUSION:In this pilot study, a relationship between the microbiota composition and monocyte homeostasis could not be firmly established. However, we identify multivariate associations between clinical factors and monocyte reconstitution post-HCT. Our findings encourage further longitudinal surveillance of the intestinal microbiome and its link to immune reconstitution.

关键词： Immune reconstitution bone marrow transplantation microbiome monocytes

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Precision medicine review: rare driver mutations and their biophysical classification

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Biophysical Reviews 2019年第1期11卷 5-19页

作者： Nussinov, Ruth Jang, Hyunbum Tsai, Chung-Jung Cheng, Feixiong Cancer and Inflammation Program Leidos Biomedical Research Inc. Frederick National Laboratory for Cancer Research National Cancer Institute 1050 Boyles St. Frederick 21702 MD United States Department of Human Molecular Genetics and Biochemistry Sackler School of Medicine Tel Aviv University Tel Aviv 69978 Israel Genomic Medicine Institute Lerner Research Institute Cleveland Clinic Cleveland 44106 OH United States Department of Molecular Medicine Cleveland Clinic Lerner College of Medicine Case Western Reserve University Cleveland 44195 OH United States Case Comprehensive Cancer Center Case Western Reserve University School of Medicine Cleveland 44106 OH United States

How can biophysical principles help precision medicine identify rare driver mutations? A major tenet of pragmatic approaches to precision oncology and pharmacology is that driver mutations are very frequent. However, frequency is a statistical attribute, not a mechanistic one. Rare mutations can also act through the same mechanism, and as we discuss below, “latent driver” mutations may also follow the same route, with “helper” mutations. Here, we review how biophysics provides mechanistic guidelines that extend precision medicine. We outline principles and strategies, especially focusing on mutations that drive cancer. Biophysics has contributed profoundly to deciphering biological processes. However, driven by data science, precision medicine has skirted some of its major tenets. Data science embodies genomics, tissue- and cell-specific expression levels, making it capable of defining genome- and systems-wide molecular disease signatures. It classifies cancer driver genes/mutations and affected pathways, and its associated protein structural data guide drug discovery. Biophysics complements data science. It considers structures and their heterogeneous ensembles, explains how mutational variants can signal through distinct pathways, and how allo-network drugs can be harnessed. Biophysics clarifies how one mutation—frequent or rare—can affect multiple phenotypic traits by populating conformations that favor interactions with other network modules. It also suggests how to identify such mutations and their signaling consequences. Biophysics offers principles and strategies that can help precision medicine push the boundaries to transform our insight into biological processes and the practice of personalized medicine. By contrast, “phenotypic drug discovery,” which capitalizes on physiological cellular conditions and first-in-class drug discovery, may not capture the proper molecular variant. This is because variants of the same protein can express more than one phenoty

关键词： Conformational ensembles Deep sequencing Drug discovery Genomics KRas Machine learning Pharmacology Phenotypic drug discovery Proteomics Ras Signaling pathways

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In vivo tropism of Salmonella Typhi toxin to cells expressing a multiantennal glycan receptor (vol 3. pg 155, 2018)

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NATURE MICROBIOLOGY 2019年第7期4卷 1242-1242页

作者： Yang, Yi-An Lee, Sohyoung Zhao, Jun Thompson, Andrew J. McBride, Ryan Tsogtbaatar, Buyankhishig Paulson, James C. Nussinov, Ruth Deng, Lingquan Song, Jeongmin Department of Microbiology and Immunology College of Veterinary Medicine Cornell University Ithaca New York USA Cancer and Inflammation Program National Cancer Institute Frederick USA Department of Molecular Medicine The Scripps Research Institute La Jolla USA Basic Science Program Leidos Biomedical Research Inc. Cancer and Inflammation Program National Cancer Institute Frederick USA Sackler Institute of Molecular Medicine Department of Human Genetics and Molecular Medicine Sackler School of Medicine Tel Aviv University Tel Aviv Israel Department of Pathology School of Medicine Johns Hopkins University Baltimore USA

An amendment to this paper has been published and can be accessed via a link at the top of the paper.

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Early life high fructose impairs microglial phagocytosis and neurodevelopment

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Nature 2025年 2025 Jun 11页

作者： Zhaoquan Wang Allie Lipshutz Celia Martínez de la Torre Alissa J Trzeciak Zong-Lin Liu Isabella C Miranda Tomi Lazarov Ana C Codo Jesús E Romero-Pichardo Achuth Nair Tanya Schild Waleska Saitz Rojas Pedro H V Saavedra Ann K Baako Kelvin Fadojutimi Michael S Downey Frederic Geissmann Giuseppe Faraco Li Gan Jon Iker Etchegaray Christopher D Lucas Marina Tanasova Christopher N Parkhurst Melody Y Zeng Kayvan R Keshari Justin S A Perry Immunology Program Sloan Kettering Institute Memorial Sloan Kettering Cancer Center New York NY USA. Immunology and Microbial Pathogenesis Program Weill Cornell Medicine New York NY USA. Department of Radiology Sloan Kettering Institute Memorial Sloan Kettering Cancer Center New York NY USA. Molecular Pharmacology Program Sloan Kettering Institute Memorial Sloan Kettering Cancer Center New York NY USA. Division of Pulmonary and Critical Care Medicine Weill Cornell Medicine New York NY USA. Louis V. Gerstner Jr Graduate School of Biomedical Sciences Memorial Sloan Kettering Cancer Center New York NY USA. Department of Biology Northeastern University Boston MA USA. Neuroscience Graduate Program Weill Cornell Medicine New York NY USA. Feil Family Brain and Mind Research Institute Weill Cornell Medicine New York NY USA. Helen and Robert Appel Alzheimer's Disease Research Institute Feil Family Brain and Mind Research Institute Weill Cornell Medicine New York NY USA. Department of Pathology and Immunology Washington University School of Medicine St Louis MO USA. Aging and Metabolism Research Program Oklahoma Medical Research Foundation Oklahoma City OK USA. University of Edinburgh Centre for Inflammation Research Queen's Medical Research Institute Edinburgh UK. Institute for Regeneration and Repair Edinburgh UK. Department of Chemistry Michigan Technological University Houghton MI USA. Health Research Institute Michigan Technological University Houghton MI USA. Gale and Ira Drukier Institute for Children's Health Weill Cornell Medicine New York NY USA. Department of Pediatrics Neonatal Medicine Weill Cornell Medicine New York NY USA. Immunology Program Sloan Kettering Institute Memorial Sloan Kettering Cancer Center New York NY USA. perryj@***. Immunology and Microbial Pathogenesis Program Weill Cornell Medicine New York NY USA. perryj@***. Louis V. Gerstner Jr Graduate School of Biomedical Sciences Memorial Sloan Kettering Cancer Cente

Despite the success of fructose as a low-cost food additive, epidemiological evidence suggests that high fructose consumption during pregnancy or adolescence is associated with disrupted neurodevelopment. An essential step in appropriate mammalian neurodevelopment is the phagocytic elimination of newly formed neurons by microglia, the resident professional phagocyte of the central nervous system. Whether high fructose consumption in early life affects microglial phagocytosis and whether this directly affects neurodevelopment remains unknown. Here we show that offspring born to female mice fed a high-fructose diet and neonates exposed to high fructose exhibit decreased phagocytic activity in vivo. Notably, deletion of the high-affinity fructose transporter GLUT5 (also known as SLC2A5) in neonatal microglia completely reversed microglia phagocytic dysfunction, suggesting that high fructose directly affects neonatal development by suppressing microglial phagocytosis. Mechanistically, we found that high-fructose treatment of mouse and human microglia suppresses phagocytosis capacity, which is rescued in GLUT5-deficient microglia. Additionally, we found that high fructose drives significant GLUT5-dependent fructose uptake and catabolism to fructose 6-phosphate, rewiring microglial metabolism towards a hypo-phagocytic state in part by enforcing mitochondrial localization of the enzyme hexokinase 2. Mice exposed to high fructose as neonates develop anxiety-like behaviour as adolescents-an effect that is rescued in GLUT5-deficient mice. Our findings provide a mechanistic explanation for the epidemiological observation that high-fructose exposure during early life is associated with increased prevalence of adolescent anxiety disorders.

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Multi-omics: Differential expression of IFN-γ results in distinctive mechanistic features linking chronic inflammation, gut dysbiosis, and autoimmune diseases

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Journal of Autoimmunity 2020年 111卷 102436-102436页

作者： Bae, Heekyong R. Leung, Patrick S.C. Hodge, Deborah L. Fenimore, John M. Jeon, Seon-Min Thovarai, Vishal Dzutsev, Amiran Welcher, Andrew A. Boedigheimer, Michael Damore, Michael A. Choi, Myung-Sook Fravell, Richard A. Trinchieri, Giorgio Gershwin, M. Eric Young, Howard A. Laboratory of Experimental Immunology Cancer and Inflammation Program Center for Cancer Research National Cancer Institute-Frederick Frederick MD United States Division of Rheumatology Allergy and Clinical Immunology University of California at Davis Davis CA United States Center for Food and Nutritional Genomics Research Department of Food Science and Nutrition Kyungpook National University Daegu South Korea Amgen Inc. Thousand Oaks CA United States Department of Immunology Yale School of Medicine New Haven CT United States

Low grade, chronic inflammation is a critical risk factor for immunologic dysfunction including autoimmune diseases. However, the multiplicity of complex mechanisms and lack of relevant murine models limit our understanding of the precise role of chronic inflammation. To address these hurdles, we took advantage of multi-omics data and a unique murine model with a low but chronic expression of IFN-γ, generated by replacement of the AU-rich element (ARE) in the 3’ UTR region of IFN-γ mRNA with random nucleotides. Herein, we demonstrate that low but differential expression of IFN-γ in mice by homozygous or heterozygous ARE replacement triggers distinctive gut microbial alterations, of which alteration is female-biased with autoimmune-associated microbiota. Metabolomics data indicates that gut microbiota-dependent metabolites have more robust sex-differences than microbiome profiling, particularly those involved in fatty acid oxidation and nuclear receptor signaling. More importantly, homozygous ARE-Del mice have dramatic changes in tryptophan metabolism, bile acid and long-chain lipid metabolism, which interact with gut microbiota and nuclear receptor signaling similarly with sex-dependent metabolites. Consistent with these findings, nuclear receptor signaling, encompassing molecules such as PPARs, FXR, and LXRs, was detectable as a top canonical pathway in comparison of blood and tissue-specific gene expression between female homozygous vs heterozygous ARE-Del mice. Further analysis implies that dysregulated autophagy in macrophages is critical for breaking self-tolerance and gut homeostasis, while pathways interact with nuclear receptor signaling to regulate inflammatory responses. Overall, pathway-based integration of multi-omics data provides systemic and cellular insights about how chronic inflammation driven by IFN-γ results in the development of autoimmune diseases with specific etiopathological features. © 2020

关键词： Autoimmune diseases Autophagy Chronic inflammation Gut dysbiosis Interferons Multi-omics Nuclear receptors Sex-difference

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Infection Trains the Microbiota for Enhanced Resistance to Pathogens

SSRN

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SSRN 2020年

作者： Stacy, Apollo Andrade-Oliveira, Vinicius McCulloch, John A. Hild, Benedikt Oh, Ji Hoon Perez-Chaparro, P. Juliana Sim, Choon K. Trinchieri, Giorgio Segre, Julia A. Rehermann, Barbara Belkaid, Yasmine Metaorganism Immunity Section Laboratory of Immune System Biology National Institute of Allergy and Infectious Diseases BethesdaMD20892 United States NIAID Microbiome Program National Institute of Allergy and Infectious Diseases BethesdaMD20892 United States Postdoctoral Research Associate Training Program National Institute of General Medical Sciences BethesdaMD20892 United States Cancer and Inflammation Program Center for Cancer Research National Cancer Institute BethesdaMD20892 United States Immunology Section Liver Diseases Branch National Institute of Diabetes and Digestive and Kidney Diseases National Institutes of Health DHHS BethesdaMD20892 United States Microbial Genomics Section Translational and Functional Genomics Branch National Human Genome Research Institute BethesdaMD20892 United States

The microbiota shields the host against infections in a process known as colonization resistance. How infections themselves shape this fundamental process remains largely unknown. Here, we show that gut microbiota from previously infected hosts display enhanced resistance to infections. This long-term functional remodeling is associated with altered bile acid metabolism leading to the expansion of taxa that utilize the sulfonic acid taurine. Notably, supplying exogenous taurine alone is sufficient to induce this alteration in microbiota function and enhance resistance. Mechanistically, taurine potentiates the microbiota’s production of sulfide, an inhibitor of cellular respiration, which is key to host invasion by numerous pathogens. As such, pharmaceutical sequestration of sulfide perturbs the microbiota’s composition and promotes pathogen invasion. Together, this work reveals a process, akin to the immune system’s capacity for training, by which the host can deploy taurine as a prebiotic to nourish and educate the microbiota, promoting its resistance to infection. © 2020, The Authors. All rights reserved.

关键词： Bacteria

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Homeostatic IL-13 in healthy skin directs dendritic cell differentiation to promote TH2 and inhibit TH17 cell polarization (vol 22, pg 1538, 2021)

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NATURE IMMUNOLOGY 2022年第6期23卷 985-985页

作者： Mayer, Johannes U. Hilligan, Kerry L. Chandler, Jodie S. Eccles, David A. Old, Samuel I. Domingues, Rita G. Yang, Jianping Webb, Greta R. Munoz-Erazo, Luis Hyde, Evelyn J. Wakelin, Kirsty A. Tang, Shiau-Choot Chappell, Sally C. von Daake, Sventja Brombacher, Frank Mackay, Charles R. Sher, Alan Tussiwand, Roxane Connor, Lisa M. Gallego-Ortega, David Jankovic, Dragana Le Gros, Graham Hepworth, Matthew R. Lamiable, Olivier Ronchese, Franca Malaghan Institute of Medical Research Wellington New Zealand Immunobiology Section Laboratory of Parasitic Diseases National Institute of Allergy and Infectious Diseases National Institutes of Health Bethesda MD USA Lydia Becker Institute of Immunology and Inflammation Manchester Collaborative Centre for Inflammation Research Faculty of Biology Medicine and Health University of Manchester Manchester Academic Health Science Centre Manchester UK International Centre for Genetic Engineering and Biotechnology (ICGEB) Cape Town component & Institute of Infectious Diseases and Molecular Medicine (IDM) Division of Immunology Health Science Faculty University of Cape Town Cape Town South Africa Infection and Immunity Program Monash Biomedicine Discovery Institute Monash University Melbourne VIC Australia Department of Biomedicine University of Basel Basel Switzerland Immune Regulation Unit National Institute of Dental and Craniofacial Research National Institutes of Health Bethesda MD USA The Kinghorn Cancer Centre Garvan Institute of Medical Research Darlinghurst NSW Australia Centre for Single-Cell Technology School of Biomedical Engineering Faculty of Engineering and IT University of Technology Sydney Ultimo NSW Australia Immunoparasitology Unit Laboratory of Parasitic Diseases National Institute of Allergy and Infectious Diseases National Institutes of Health Bethesda MD USA

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Chemokines in homeostasis and diseases

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Cellular & Molecular Immunology 2018年第4期15卷 324-334页

作者： Keqiang Chen Zhiyao Bao Peng Tang Wanghua Gong Teizo Yoshimura Ji Ming Wang Cancer and Inflammation Program Center for Cancer ResearchNational Cancer Institute at FrederickFrederickMD 21702USA Department of Pulmonary&Critical Care Medicine Ruijin HospitalShanghai Jiaotong University School of MedicineShanghai 200025P.R.China Department of Breast Surgery Southwest HospitalThird Military Medical UniversityChongqing 400038China Basic Research Program Leidos Biomedical ResearchInc.FrederickMD 21702USA Department of Pathology and Experimental Medicine Graduate School of MedicineDentistry and Pharmaceutical SciencesOkayama UniversityOkayama 700-8558Japan

For the past twenty years,chemokines have emerged as a family of critical mediators of cell migration during immune surveillance,development,inflammation and cancer *** bind to seven transmembrane G protein-coupled receptors(GPCRs)that are expressed by a wide variety of cell types and cause conformational changes in trimeric G proteins that trigger the intracellular signaling pathways necessary for cell movement and *** chemokines have evolved to benefit the host,inappropriate regulation or utilization of these small proteins may contribute to or even cause ***,understanding the role of chemokines and their GPCRs in the complex physiological and diseased microenvironment is important for the identification of novel therapeutic *** review introduces the functional array and signals of multiple chemokine GPCRs in guiding leukocyte trafficking as well as their roles in homeostasis,inflammation,immune responses and cancer.

关键词： chemokines chemotaxis diseases GPCRs homeostasis inflammatory cells

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Universality of biochemical feedback and its application to immune cells

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Physical Review E 2019年第2期99卷 022422-022422页

作者： Amir Erez Tommy A. Byrd Robert M. Vogel Grégoire Altan-Bonnet Andrew Mugler Department of Molecular Biology Princeton University Princeton New Jersey 08544 USA Department of Physics and Astronomy Purdue University West Lafayette Indiana 47907 USA IBM T. J. Watson Research Center Yorktown Heights New York 10598 USA Immunodynamics Group Cancer and Inflammation Program National Cancer Institute National Institutes of Health Bethesda Maryland 20814 USA

We map a class of well-mixed stochastic models of biochemical feedback in steady state to the mean-field Ising model near the critical point. The mapping provides an effective temperature, magnetic field, order parameter, and heat capacity that can be extracted from biological data without fitting or knowledge of the underlying molecular details. We demonstrate this procedure on fluorescence data from mouse T cells, which reveals distinctions between how the cells respond to different drugs. We also show that the heat capacity allows inference of the absolute molecule number from fluorescence intensity. We explain this result in terms of the underlying fluctuations, and we demonstrate the generality of our work.

关键词： Biochemistry Cell processes & properties Fluctuations & noise Nonequilibrium statistical mechanics Phase transitions Stochastic processes Stochastic dynamical systems Critical phenomena Scaling methods

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Retinoic acid-related orphan receptor γ (RORγ): Connecting sterol metabolism to regulation of the immune system and autoimmune disease

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Current Opinion in Toxicology 2018年 8卷 66-80页

作者： Jetten, Anton M. Takeda, Yukimasa Slominski, Andrzej Kang, Hong Soon Cell Biology Section Immunity Inflammation and Disease Laboratory National Institute of Environmental Health Sciences National Institutes of Health Research Triangle Park 27709 NC United States Department of Dermatology Comprehensive Cancer Center Cancer Chemoprevention Program University of Alabama at Birmingham Birmingham 35249 AL United States

Cholesterol and its metabolites are bioactive lipids that interact with and regulate the activity of various proteins and signaling pathways that are implicated in the control of a variety of physiological and pathological processes. Recent studies revealed that retinoic acid-related orphan receptors, RORα and γ, members of the ligand-dependent nuclear receptor superfamily, exhibit quite a wide binding specificity for a number of sterols. Several cholesterol intermediates and metabolites function as natural ligands of RORα and RORγ and act as agonists or inverse agonists. Changes in cholesterol homeostasis that alter the level or type of sterol metabolites in cells, can either enhance or inhibit ROR transcriptional activity that subsequently result in changes in the physiological processes regulated by RORs, including various immune responses and metabolic pathways. Consequently, this might negatively or positively impact pathologies, in which RORs are implicated, such as autoimmune disease, inflammation, metabolic syndrome, cancer, and several neurological disorders. Best studied are the links between cholesterol metabolism, RORγt activity, and their regulation of Th17 differentiation and autoimmune disease. The discovery that Th17-dependent inflammation is significantly attenuated in RORγ-deficient mice in several experimental autoimmune disease models, initiated a search for ROR modulators that led to the identification of a number of small molecular weight RORγ inverse agonists. The inverse agonists suppress Th17 differentiation and IL-17 production and protect against autoimmunity. Together, these studies suggest that RORγt may provide an attractive therapeutic target in the management of several (inflammatory) diseases. © 2018 Elsevier B.V.

关键词： (Inverse) agonists Autoimmune disease Cholesterol biosynthesis inflammation Metabolism Oxysterols Retinoic acid-related orphan receptor RORγ Th17 cells Transcription Vitamin D3

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