14 results on '"Kevin S. Bonham"'
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2. Microclimate is a strong predictor of the native and invasive plant-associated soil microbiota on San Cristóbal Island, Galápagos archipelago
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Alexi A. Schoenborn, Sarah M. Yannarell, Caroline T. MacVicar, Noelia N. Barriga-Medina, Meng Markillie, Hugh Mitchell, Kevin S. Bonham, Antonio Leon-Reyes, Diego Riveros-Iregui, Vanja Klepac-Ceraj, and Elizabeth A. Shank
- Abstract
Understanding the major drivers that influence soil bacterial and fungal communities is essential to mitigate the impacts of human activity on vulnerable ecosystems, like those found on the Galápagos Islands. Located ~1000 km off the coast of Ecuador, the volcanically formed islands are situated within distinct oceanic currents, which provide seasonal weather patterns and unique microclimates within small spatial scales across the islands. Although much is known about the impacts of human activity, such as climate change and invasive plant species, on above ground biodiversity of the Galápagos Islands, little is known about the resident soil microbial communities and the drivers that shape these communities. Here, our goal was to investigate the bacterial and fungal communities found in soil located in three distinct microclimates: Mirador (arid), Cerro Alto (transition zone), and El Junco (humid), and associated with native and invasive plant types. At each site, we collected soil at three depths (rhizosphere, 5 cm, and 15 cm) associated with the invasive plant, Psidium guajava (guava), and native plant types. We determined that the sampling location (microclimate) was the strongest driver of both bacterial and fungal communities (74 and 38%, respectively), with additional minor but significant impacts from plant type and soil depth. This study highlights the continued need to explore microbial communities across diverse environments and demonstrates the weight of different abiotic and biotic factors impacting soil microbial communities across San Cristóbal Island in the Galápagos archipelago.IMPORTANCE/SIGNIFICANCEHuman activity such as climate change, pollution, introduction of invasive species, and deforestation, poses a huge threat to biodiverse environments. Soil microbiota are an essential component to maintaining healthy ecosystems. However, a greater understanding of factors that alter these microbial communities is needed in order to find ways to mitigate and reverse the impacts imposed by human activity. The Galápagos Islands are a unique real-world laboratory, in that the islands’ biogeography and physical locations in the Pacific Ocean provide distinct microclimates within small geographic distances. Harnessing these distinct environments allowed us to investigate the influence of microclimates, soil depth, and vegetation cover on bacterial and fungal community composition.
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- 2022
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3. Targeted High-Resolution Taxonomic Identification of
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Lauren, Tso, Kevin S, Bonham, Alyssa, Fishbein, Sophie, Rowland, and Vanja, Klepac-Ceraj
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child development ,metagenomics ,Milk, Human ,Infant, Newborn ,food and beverages ,Infant ,Oligosaccharides ,comparative genomics ,Bifidobacterium longum ,Article ,human milk oligosaccharide metabolizing genes ,metabolic potential ,Gastrointestinal Microbiome ,Cohort Studies ,Feces ,Bifidobacterium infantis ,Breast Feeding ,Bacterial Proteins ,Genes, Bacterial ,Humans ,pediatric cohort - Abstract
Bifidobacterium longum subsp. infantis (B. infantis) is one of a few microorganisms capable of metabolizing human breast milk and is a pioneer colonizer in the guts of breastfed infants. One current challenge is differentiating B. infantis from its close relatives, B. longum and B. suis. All three organisms are classified in the same species group but only B. infantis can metabolize human milk oligosaccharides (HMOs). We compared HMO-metabolizing genes across different Bifidobacterium genomes and developed B. infantis-specific primers to determine if the genes alone or the primers can be used to quickly characterize B. infantis. We showed that B. infantis is uniquely identified by the presence of five HMO-metabolizing gene clusters, tested for its prevalence in infant gut metagenomes, and validated the results using the B. infantis-specific primers. We observed that only 15 of 203 (7.4%) children under 2 years old from a cohort of US children harbored B. infantis. These results highlight the importance of developing and improving approaches to identify B. infantis. A more accurate characterization may provide insights into regional differences of B. infantis prevalence in infant gut microbiota.
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- 2021
4. Multi-omics of the gut microbial ecosystem in inflammatory bowel diseases
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Nadim J. Ajami, Gholamali Rahnavard, Melanie Schirmer, Ashwin N. Ananthakrishnan, Kevin S. Bonham, Lee A. Denson, Clary B. Clish, Kathleen Lake, Yoshiki Vázquez-Baeza, Dermot P.B. McGovern, David Casero, Dmitry Shungin, Jonathan Braun, Antonio Gonzalez, Mahadev Prasad, Thomas G. Graeber, Joseph F. Petrosino, Carol J. Landers, Damian R. Plichta, Hera Vlamakis, Subra Kugathasan, Jenny S. Sauk, Janet K. Jansson, Elizabeth Andrews, Rob Knight, A. Brantley Hall, Harland S. Winter, Richard A. White, Curtis Huttenhower, Himel Mallick, Colin J. Brislawn, Tiffany W. Poon, Holly Courtney, Eric A. Franzosa, Julian Avila-Pacheco, Thaddeus S. Stappenbeck, Jason Lloyd-Price, Ramnik J. Xavier, and Cesar Arze
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Proteomics ,0301 basic medicine ,Systems analysis ,Disease ,Biology ,Inflammatory bowel disease ,Article ,Clostridia ,03 medical and health sciences ,0302 clinical medicine ,Species Specificity ,Biopsy ,medicine ,Animals ,Humans ,Ecosystem ,Phylogeny ,Multidisciplinary ,medicine.diagnostic_test ,Fungi ,Obligate anaerobe ,Inflammatory Bowel Diseases ,medicine.disease ,biology.organism_classification ,Ulcerative colitis ,Gastrointestinal Microbiome ,3. Good health ,Crohn's disease ,030104 developmental biology ,Health ,Viruses ,Immunology ,030211 gastroenterology & hepatology ,Microbiome ,Transcriptome ,Dysbiosis ,Biomarkers ,Human Microbiome Project - Abstract
Inflammatory bowel diseases, which include Crohn’s disease and ulcerative colitis, affect several million individuals worldwide. Crohn’s disease and ulcerative colitis are complex diseases that are heterogeneous at the clinical, immunological, molecular, genetic, and microbial levels. Individual contributing factors have been the focus of extensive research. As part of the Integrative Human Microbiome Project (HMP2 or iHMP), we followed 132 subjects for one year each to generate integrated longitudinal molecular profiles of host and microbial activity during disease (up to 24 time points each; in total 2,965 stool, biopsy, and blood specimens). Here we present the results, which provide a comprehensive view of functional dysbiosis in the gut microbiome during inflammatory bowel disease activity. We demonstrate a characteristic increase in facultative anaerobes at the expense of obligate anaerobes, as well as molecular disruptions in microbial transcription (for example, among clostridia), metabolite pools (acylcarnitines, bile acids, and short-chain fatty acids), and levels of antibodies in host serum. Periods of disease activity were also marked by increases in temporal variability, with characteristic taxonomic, functional, and biochemical shifts. Finally, integrative analysis identified microbial, biochemical, and host factors central to this dysregulation. The study’s infrastructure resources, results, and data, which are available through the Inflammatory Bowel Disease Multi’omics Database (http://ibdmdb.org), provide the most comprehensive description to date of host and microbial activities in inflammatory bowel diseases., The Inflammatory Bowel Disease Multi’omics Database includes longitudinal data encompassing a multitude of analyses of stool, blood and biopsies of more than 100 individuals, and provides a comprehensive description of host and microbial activities in inflammatory bowel diseases.
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- 2019
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5. Deep-sea microbes as tools to refine the rules of innate immune pattern recognition
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Randi D. Rotjan, Jonathan C. Kagan, Timothy M. Shank, Kevin S. Bonham, Robert K. Ernst, David R. Goodlett, Erik E. Cordes, Richard J.H. Smith, Valentina Poli, Francesca M. Gardner, Anna E. Gauthier, Ivan Zanoni, Aranteiti Tekiau, Courtney E. Chandler, and Steven J. Biller
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0301 basic medicine ,Aquatic Organisms ,Lipopolysaccharide ,Oceans and Seas ,030106 microbiology ,Immunology ,Biology ,Article ,Cell Line ,Cell wall ,Mice ,03 medical and health sciences ,chemistry.chemical_compound ,Immune system ,Species Specificity ,Animals ,Humans ,Seawater ,Receptor ,Innate immune system ,Host Microbial Interactions ,business.industry ,Microbiota ,Pattern recognition receptor ,Pattern recognition ,General Medicine ,biology.organism_classification ,030104 developmental biology ,chemistry ,Receptors, Pattern Recognition ,Pattern recognition (psychology) ,Artificial intelligence ,Water Microbiology ,business ,Biomarkers ,Bacteria - Abstract
The assumption of near-universal bacterial detection by pattern recognition receptors is a foundation of immunology. The limits of this pattern recognition concept, however, remain undefined. As a test of this hypothesis, we determined whether mammalian cells can recognize bacteria that they have never had the natural opportunity to encounter. These bacteria were cultivated from the deep Pacific Ocean, where the genus Moritella was identified as a common constituent of the culturable microbiota. Most deep-sea bacteria contained cell wall lipopolysaccharide (LPS) structures that were expected to be immunostimulatory, and some deep-sea bacteria activated inflammatory responses from mammalian LPS receptors. However, LPS receptors were unable to detect 80% of deep-sea bacteria examined, with LPS acyl chain length being identified as a potential determinant of immunosilence. The inability of immune receptors to detect most bacteria from a different ecosystem suggests that pattern recognition strategies may be defined locally, not globally.
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- 2021
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6. Comparative analysis of 16S rRNA gene and metagenome sequencing in pediatric gut microbiomes
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Danielle Peterson, Kevin S. Bonham, Sophie Rowland, Cassandra W. Pattanayak, RESONANCE Consortium, Vanja Klepac-Ceraj, Sean C. L. Deoni, Viren D’Sa, Muriel Bruchhage, Alexandra Volpe, Jennifer Beauchemin, Caroline Wallace, John Rogers, Rosa Cano, Jessica Fernandes, Elizabeth Walsh, Brittany Rhodes, Matthew Huentelman, Candace Lewis, Matthew D. De Both, Marcus A. Naymik, Susan Carnell, Elena Jansen, Jennifer R. Sadler, Gita Thapaliya, Kevin Bonham, Monique LeBourgeois, Hans Georg Mueller, Jane-Ling Wang, Changbo Zhu, Yaqing Chen, and Joseph Braun
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Microbiology (medical) ,amplicon sequencing ,Human microbiome ,gut microbiome ,Shotgun ,Computational biology ,Biology ,Amplicon ,16S ribosomal RNA ,Microbiology ,QR1-502 ,metagenome ,Deep sequencing ,sequencing depth ,Metagenomics ,pediatric cohort ,16S rRNA gene ,Microbiome ,Gene ,Original Research - Abstract
The colonization of the human gut microbiome begins at birth, and, over time, these microbial communities become increasingly complex. Most of what we currently know about the human microbiome, especially in early stages of development, was described using culture-independent sequencing methods that allow us to identify the taxonomic composition of microbial communities using genomic techniques, such as amplicon or shotgun metagenomic sequencing. Each method has distinct tradeoffs, but there has not been a direct comparison of the utility of these methods in stool samples from very young children, which have different features than those of adults. We compared the effects of profiling the human infant gut microbiome with 16S rRNA amplicon versus shotgun metagenomic sequencing techniques in 130 fecal samples; younger than 15, 15-30, and older than 30 months of age. We demonstrate that observed changes in alpha-diversity and beta-diversity with age occur to similar extents using both profiling methods. We also show that 16S rRNA profiling identified a larger number of genera and we find several genera that are missed or underrepresented by each profiling method. We present the link between alpha diversity and shotgun metagenomic sequencing depth for children of different ages. These findings provide a guide for selecting an appropriate method and sequencing depth for the three studied age groups.
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- 2021
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7. Gut-resident microorganisms and their genes are associated with cognition and neuroanatomy in children
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Muriel M.K. Bruchhage, Lexie Volpe, Curtis Huttenhower, Sean C.L. Deoni, Vanja Klepac-Ceraj, Kellyn Dyer, Sophie Rowland, Kevin S. Bonham, and Viren D'Sa
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0303 health sciences ,Cerebellum ,Central nervous system ,Glutamate receptor ,Cognition ,Biology ,medicine.disease ,03 medical and health sciences ,0302 clinical medicine ,medicine.anatomical_structure ,Ruminococcus gnavus ,medicine ,Autism ,Microbiome ,Neuroscience ,030217 neurology & neurosurgery ,030304 developmental biology ,Neuroanatomy - Abstract
The gastrointestinal tract, its resident microorganisms, and the central nervous system are connected by biochemical signaling, also known as "microbiome-gut-brain-axis." Both the human brain and the gut microbiome have critical developmental windows in the first years of life, raising the possibility that their development is co-occurring and likely co-dependent. Emerging evidence implicates gut microorganisms and microbiota composition in cognitive outcomes and neurodevelopmental disorders (e.g., autism and anxiety), but the influence of gut microbial metabolism on typical neurodevelopment has not been explored in detail. We investigated the relationship of the microbiome with the neuroanatomy and cognitive function of 361 healthy children, demonstrating that differences in gut microbial taxa and gene functions are associated with overall cognitive function and with differences in the size of multiple brain regions. Using a combination of multivariate linear and machine learning (ML) models, we showed that many species, including Gordonibacter pamelae and Blautia wexlerae, were significantly associated with higher cognitive function, while some species such as Ruminococcus gnavus were more commonly found in children with low cognitive scores after controlling for sociodemographic factors. Microbial genes for enzymes involved in the metabolism of neuroactive compounds, particularly short-chain fatty acids such as acetate and propionate, were also associated with cognitive function. In addition, ML models were able to use microbial taxa to predict the volume of brain regions, and many taxa that were identified as important in predicting cognitive function also dominated the feature importance metric for individual brain regions. For example, B. wexlerae was the most important species in models predicting the size of the parahippocampal region in both the left and right hemispheres, while several species from the phylum Bacteroidetes, including GABA-producing B. ovatus, were important for predicting the size of the left accumbens area, but not the right. These findings provide potential biomarkers of neurocognition and brain development and may lead to the future development of targets for early detection and early intervention.
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- 2020
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8. Microbiome.jl and BiobakeryUtils.jl - Julia packages for working with microbial community data
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Annelle Abatoni Kayisire, Vanja Klepac-Ceraj, Kevin S. Bonham, and Anika S. Luo
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Microbial population biology ,Ecology ,Microbiome ,Biology - Published
- 2021
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9. The Prevotella copri complex comprises four distinct clades that are underrepresented in Westernised populations
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Federica Armanini, John Lusingu, Maria Carmen Collado, Francesco Asnicar, Paolo Manghi, Kevin S. Bonham, Thomas Rattei, Francesca De Filippis, Nicola Segata, Frank Maixner, Dan R. Littman, Omar Rota-Stabelli, Richard Bonneau, Lars Engstrand, Adrian Tett, Cara Magnabosco, Nicolai Karcher, Albert Zink, Kun D. Huang, Moreno Zolfo, Karl J. Reinhard, Danilo Ercolini, Edoardo Pasolli, Hannah Fehlner-Peach, John H Amuasi, Daniel Eibach, Curtis Huttenhower, and Fredrik Boulund
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0303 health sciences ,03 medical and health sciences ,Global population ,0302 clinical medicine ,Human gut ,Evolutionary biology ,Prevotella copri ,Biology ,Clade ,Genome ,030217 neurology & neurosurgery ,030304 developmental biology - Abstract
Prevotella copri is a common inhabitant of the human gut. Interest in P. copri has gathered pace due to conflicting reports on whether it is beneficial or detrimental to health. In a cross-continent meta-analysis exploiting >6,500 available metagenomes supported by new isolate sequencing and recovery of high-quality genomes from metagenomes, we obtained >1,000 P. copri genomes. This 100-fold increase over existing isolate genomes allowed the genetic and global population structure of P. copri to be explored at an unprecedented depth. We demonstrate P. copri is not a monotypic species, but encompasses four distinct clades (>10% inter-clade vs. P. copri complex, comprising clades A, B, C and D. We show the complex is near ubiquitous in non-Westernised populations (95.4% versus 29.6% in Westernised populations), where all four clades are typically co-present within an individual (61.6% of the cases), in contrast to Westernised populations (4.6%). Genomic analysis of the complex reveals substantial and complementary functional diversity, including the potential for utilisation of complex carbohydrates, suggestive that multi-generational dietary modifications may be a driver for the reduced P. copri prevalence in Westernised populations. Analysis of ancient stool microbiomes highlights a similar pattern of P. copri presence consistent with modern non-Westernised populations, allowing us to estimate the time of clade delineation to pre-date human migratory waves out of Africa. Our analysis reveals P. copri to be far more diverse than previously appreciated and this diversity appears to be underrepresented in Western-lifestyle populations.
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- 2019
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10. Author response: Extensive horizontal gene transfer in cheese-associated bacteria
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Kevin S. Bonham, Rachel J. Dutton, and Benjamin E. Wolfe
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Horizontal gene transfer ,Associated bacteria ,Biology ,Microbiology - Published
- 2017
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11. The Prevotella copri Complex Comprises Four Distinct Clades Underrepresented in Westernized Populations
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Edoardo Pasolli, Richard Bonneau, Francesca De Filippis, Albert Zink, Cara Magnabosco, Lars Engstrand, Adrian Tett, Karl J. Reinhard, Nicolai Karcher, Dan R. Littman, Daniel Eibach, Fredrik Boulund, Francesco Asnicar, Paolo Manghi, John Lusingu, Thomas Rattei, Kevin S. Bonham, Nicola Segata, Omar Rota-Stabelli, Danilo Ercolini, Curtis Huttenhower, John H Amuasi, Frank Maixner, Hannah Fehlner-Peach, Kun D. Huang, Moreno Zolfo, Federica Armanini, Maria Carmen Collado, Tett, Adrian, Huang, Kun D, Asnicar, Francesco, Fehlner-Peach, Hannah, Pasolli, Edoardo, Karcher, Nicolai, Armanini, Federica, Manghi, Paolo, Bonham, Kevin, Zolfo, Moreno, De Filippis, Francesca, Magnabosco, Cara, Bonneau, Richard, Lusingu, John, Amuasi, John, Reinhard, Karl, Rattei, Thoma, Boulund, Fredrik, Engstrand, Lar, Zink, Albert, Collado, Maria Carmen, Littman, Dan R, Eibach, Daniel, Ercolini, Danilo, Rota-Stabelli, Omar, Huttenhower, Curti, Maixner, Frank, Segata, Nicola, and European Research Council
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Bacterial phylogenetics ,bacterial pangenome ,Westernization ,gut microbe ,Biology ,Human microbiome ,Microbiology ,Genome ,Settore MED/07 - MICROBIOLOGIA E MICROBIOLOGIA CLINICA ,Article ,03 medical and health sciences ,0302 clinical medicine ,Iceman ,Virology ,Metagenomic assembly ,Bacterial pangenome ,10. No inequality ,Clade ,ancient DNA ,030304 developmental biology ,metagenomics ,0303 health sciences ,Ancient DNA ,Host (biology) ,Gut microbes ,human microbiome ,Comparative microbial genomics ,comparative microbial genomic ,Genetic divergence ,bacterial phylogenetic ,Evolutionary biology ,Metagenomics ,Prevotella copri ,metagenomic assembly ,Parasitology ,030217 neurology & neurosurgery - Abstract
Summary Prevotella copri is a common human gut microbe that has been both positively and negatively associated with host health. In a cross-continent meta-analysis exploiting >6,500 metagenomes, we obtained >1,000 genomes and explored the genetic and population structure of P. copri. P. copri encompasses four distinct clades (>10% inter-clade genetic divergence) that we propose constitute the P. copri complex, and all clades were confirmed by isolate sequencing. These clades are nearly ubiquitous and co-present in non-Westernized populations. Genomic analysis showed substantial functional diversity in the complex with notable differences in carbohydrate metabolism, suggesting that multi-generational dietary modifications may be driving reduced prevalence in Westernized populations. Analysis of ancient metagenomes highlighted patterns of P. copri presence consistent with modern non-Westernized populations and a clade delineation time pre-dating human migratory waves out of Africa. These findings reveal that P. copri exhibits a high diversity that is underrepresented in Western-lifestyle populations., Graphical Abstract, Highlights • P. copri is not a monotypic species but composed of four distinct clades • The P. copri complex is more prevalent in populations with non-Westernized lifestyles • P. copri clades are frequently co-present within non-Westernized individuals • Ancient stool samples suggest Westernization leads to P. copri underrepresentation, Tett et al. find that the intestinal microbe Prevotella copri encompasses four distinct clades constituting the P. copri complex. The complex is prevalent in non-Westernized populations where co-presence of all clades is commonly observed within individuals. Analysis of ancient stool samples supports Westernization as contributing to reduced P. copri prevalence.
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- 2019
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12. Effects of a novel arginine methyltransferase inhibitor on T-helper cell cytokine production
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M. G. Finn, Yeon-Hee Lim, Dawn M. Hill, Kerri A. Mowen, Saskia Hemmers, and Kevin S. Bonham
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chemistry.chemical_classification ,Cell growth ,Protein-Arginine N-Methyltransferases ,Cell Biology ,T helper cell ,Methylation ,Biology ,Biochemistry ,medicine.anatomical_structure ,Enzyme ,Histone ,chemistry ,medicine ,biology.protein ,Structure–activity relationship ,Molecular Biology ,Interleukin 4 - Abstract
The protein arginine methyltransferase (PRMT) family of enzymes catalyzes the transfer of methyl groups from S-adenosylmethionine to the guanidino nitrogen atom of peptidylarginine to form monomethylarginine or dimethylarginine. We created several less polar analogues of the specific PRMT inhibitor AMI-1, and one such compound was found to have improved PRMT inhibitory activity over the parent molecule. The newly identified PRMT inhibitor modulated T helper cell function and thus may serve as a lead for further inhibitors useful for immune-mediated disease treatment.
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- 2010
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13. A promiscuous lipid-binding protein diversifies the subcellular sites of toll-like receptor signal transduction
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Amaya I. Wolf, Wolfgang Weninger, Kevin S. Bonham, Kachiko Hayashi, Akiko Iwasaki, David M. Knipe, Megan H. Orzalli, Jonathan C. Kagan, and Christoph Glanemann
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TIRAP ,Endosome ,Endosomes ,Biology ,General Biochemistry, Genetics and Molecular Biology ,Article ,Proinflammatory cytokine ,03 medical and health sciences ,0302 clinical medicine ,Animals ,Receptor ,030304 developmental biology ,0303 health sciences ,Toll-like receptor ,Innate immune system ,Membrane Glycoproteins ,Biochemistry, Genetics and Molecular Biology(all) ,Macrophages ,Cell Membrane ,Toll-Like Receptors ,Receptors, Interleukin-1 ,Herpes Simplex ,Immunity, Innate ,Cell biology ,Mice, Inbred C57BL ,Myeloid Differentiation Factor 88 ,Signal transduction ,030215 immunology ,Signal Transduction - Abstract
SummaryThe Toll-like receptors (TLRs) of the innate immune system are unusual in that individual family members are located on different organelles, yet most activate a common signaling pathway important for host defense. It remains unclear how this common signaling pathway can be activated from multiple subcellular locations. Here, we report that, in response to natural activators of innate immunity, the sorting adaptor TIRAP regulates TLR signaling from the plasma membrane and endosomes. TLR signaling from both locations triggers the TIRAP-dependent assembly of the myddosome, a protein complex that controls proinflammatory cytokine expression. The actions of TIRAP depend on the promiscuity of its phosphoinositide-binding domain. Different lipid targets of this domain direct TIRAP to different organelles, allowing it to survey multiple compartments for the presence of activated TLRs. These data establish how promiscuity, rather than specificity, can be a beneficial means of diversifying the subcellular sites of innate immune signal transduction.
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- 2013
14. NIP45 controls the magnitude of the type 2 T helper cell response
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John W. Fathman, Kevin S. Bonham, Kerri A. Mowen, Laurie H. Glimcher, Saskia Hemmers, Michael J. Grusby, Daniel S. Friend, and Michael F. Gurish
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Protein-Arginine N-Methyltransferases ,T cell ,Biology ,Arginine ,Methylation ,Histones ,Mice ,Th2 Cells ,medicine ,Animals ,Enhancer ,Promoter Regions, Genetic ,Transcription factor ,Trichinella spiralis ,Regulation of gene expression ,Multidisciplinary ,NFATC Transcription Factors ,Protein arginine methyltransferase 5 ,Intracellular Signaling Peptides and Proteins ,Nuclear Proteins ,NFAT ,Trichinellosis ,T helper cell ,Biological Sciences ,Chromatin Assembly and Disassembly ,Molecular biology ,Mice, Mutant Strains ,medicine.anatomical_structure ,Gene Expression Regulation ,Cytokines ,Interleukin-4 ,Gene Deletion - Abstract
Nuclear factor of activated T cell (NFAT) transcription factors are key regulators of gene transcription within immune cells. The NFAT-interacting protein, (NIP45), augments NFAT-driven IL-4 expression by a mechanism that relies on arginine methylation. To establish the function of NIP45 in vivo, we generated mice with a targeted deletion of the gene encoding this cofactor.NIP45-deficient T helper cells displayed profound defects in the expression of NFAT-regulated cytokine genes, including IL-4. WhereasNIP45deficiency does not interfere with T helper cell NFAT activation or lineage-specific transcription-factor expression, NIP45 acts as an enhancer for the assembly of protein arginine methyltransferase 1 and the protein arginine methyltransferase 1-linked histone 4 arginine 3 methylation with the IL-4 promoter. Our study reveals an essential role for NIP45 in promoting robust cytokine expression in vivo, which is required for the efficient handling of parasites. We propose that NIP45 acts as a molecular rheostat serving to amplify the type-2 immune response.
- Published
- 2010
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