Forsyth Institute

Cambridge, MA, United States

Forsyth Institute

Cambridge, MA, United States
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News Article | January 25, 2016

This week, for the first time, scientists describe distinct bacterial assemblages living in dental plaque, which they discovered using a novel imaging approach that "cuts through the overwhelming complexity of detail in microbial communities and allows common patterns to shine through." The study appears in Proceedings of the National Academy of Sciences and was led by Jessica Mark Welch of the Marine Biological Laboratory (MBL), Woods Hole, and Gary Borisy of the Forsyth Institute, Cambridge. Plaque on teeth, the team discovered, contains micron-scaled "hedgehog" structures in which eight different kinds of bacteria are radially arranged around ninth kind, filamentous Corynebacteria. Seeing these structures offers scientists valuable information on how the bacterial members function that can't be gleaned from genomic analysis, which specifies what microbes are present in a community, but not how they are organized. "Microbes behave very differently depending on where they are and who they are next to," Mark Welch says. "They will secrete entirely different sets of chemicals and metabolites depending on who their microbial neighbors are. So, if we want to accurately describe what these microbes are doing - really, what they are - we need to know where they are." The team proposes a model for how dental plaque develops, which is based on their imaging observations combined with plaque sequencing data from the Human Microbiome Project. "This is a really exciting new way to look at microbial communities," Mark Welch says of the spectral fluorescence imaging approach they developed at MBL. "The degree of organization we found in the hedgehog structure was amazing, as was the repeated finding of the same structure in different individuals. This finding that bacteria can develop such a degree of spatial organization may be generalizable to other microbiomes. We just have to go look." Explore further: Choosing your neighbors: Scientists see how microbes relate in space More information: Biogeography of a human oral microbiome at the micron scale,

CAMBRIDGE, Mass., March 1 - A team of scientists from The Forsyth Institute and the Dasman Diabetes Institute in Kuwait have found that metabolic diseases, which are characterized by high blood pressure, high blood sugar, and obesity -- leads to changes in oral bacteria and puts people with the disease at a greater risk for poor oral health. This study of more than 8,000 ten year olds in Kuwait showed that metabolic diseases lead to increases in salivary glucose; alterations of the bacteria found in the mouth; and increased risk of cavities and gum disease. This work reinforces the need for preventive dental care and greater integration between medical and dental care. The study, titled, "The Salivary Microbiome is altered in the Presence of High Salivary Glucose," can be found on PLOS ONE. Over the past ten years, it has become clear that defining a "healthy" microbiome is a critical step for discovering how variations in the bacteria found in and on our body contribute to both disease and wellbeing. While scientists now know a great deal about what bacteria live in our mouth and throughout the body, it is still unclear whether differences in the human microbiome that are seen in many disease states are a symptom of the disease or part of the underlying cause. "The mouth represents a rich microbiome that is easily accessible," said Dr. Max Goodson, the study's lead author. "Our research is providing further evidence of the connections between the mouth and some of society's most costly and deadly systemic diseases--and of the importance of using the mouth as a tool for preventive health." We measured the glucose concentration, bacterial counts, and relative frequencies of 42 bacterial species in whole saliva samples from 8,173 Kuwaiti adolescents (mean age 10.00 ± 0.67 years) using DNA probe analysis. In addition, clinical data related to obesity, dental caries, and gingivitis were collected. Data were compared between adolescents with high salivary glucose (HSG); glucose concentration and those with low salivary glucose. Investigators found that HSG was associated with dental caries and gingivitis in the study population. The overall salivary bacterial load in saliva decreased with increasing salivary glucose concentration. Under HSG conditions, the bacterial count for 35 (83%) of 42 species was significantly reduced, and relative bacterial frequencies in 27 species (64%) were altered, as compared with LSG conditions. These alterations were stronger predictors of high salivary glucose than measures of oral disease, obesity, sleep or fitness. These observations clearly indicate that metabolic diseases, such as diabetes, that produce elevated glucose in blood and saliva can significantly alter the oral microflora. Samples were obtain through the Forsyth Kuwait Healthy Life Study, is a longitudinal cohort investigation of more than 8,000 children. Forsyth has worked with The Dasman Diabetes Institute and the Kuwait/Forsyth School program to conduct a clinical investigation of the development of obesity, metabolic syndrome and type 2 diabetes in Kuwaiti children. During the five-year study, the body weight, height, blood pressure and fitness were measured, oral disease was evaluated, nutritional information was collected, questionnaires on sleep and medical history were answered and saliva was collected for analysis. Founded in 1910, the Forsyth Institute is the only independent research organization in the United States dedicated to understanding the important connections between oral health and overall wellness. Forsyth scientists are shaping the direction of personalized medicine through pioneering biomedical research and its direct application to new diagnostics, devices and therapies. Forsyth combines its expertise in oral and associated systemic diseases with a relentless drive to ask - and answer - critical questions about how to best alleviate daily health challenges for billions. Forsyth is a not-for-profit organization that is also committed to treating underserved populations in local communities and on a national and global scale. To learn more about Forsyth, visit http://www. .

News Article | April 20, 2016

Bacteria possess the ability to take up DNA from their environment, a skill that enables them to acquire new genes for antibiotic resistance or to escape the immune response. Scientists have now mapped the core set of genes that are consistently controlled during DNA uptake in strep bacteria, and they hope the finding will allow them to cut off the microbes' ability to survive what doctors and nature can throw at them. The findings, by a team of researchers from the University of Oslo, the Forsyth Institute, and the University of Illinois at Chicago, appeared last week in the American Society for Microbiology's new open-access journal, mSystems. The researchers wanted to know precisely which metabolic pathways in the bacterial cell must be activated for the bacteria to become "competent," or able to acquire genes from DNA in the environment. They focused on Streptococcus mutans, a strain involved in tooth decay. Earlier studies of competence had pointed to more than 300 active genes. The new study identifies only 83 genes in 29 regions of the strep chromosome that are specific to the competence pathway, with 27 of these genes lying within an interconnected network controlled by one of three key regulator molecules. When the researchers compared the new results to earlier studies in five other strep species, they found that in all those species a core set of only 27 activated competence genes was required for DNA uptake. "Streptococcus is a diverse group of species that evolved from a common ancestor to adapt to diverse hosts and sugar-rich niches," says study co-author Donald Morrison, professor of biological sciences at UIC. "Our findings—that two-thirds of the core activated genes in streptococcus have transformation functions—suggest that this is an ancient response, maintained because of its value in promoting ready access to external DNA." The question now, says Morrison, is what is the function of the remaining one-third of the core genes? "We know that gene transfer can occur in their absence," the authors write, "suggesting that new aspects of competence are just waiting to be discovered." New insights in this field may pave the way to new strategies to avoid unwanted gene transfers, such as those enabling the spread of antibiotic resistance.

News Article | December 14, 2016

CAMBRIDGE, Mass., Dec.14 - Sjögren's syndrome is the second most common autoimmune disease affecting four million Americans--yet treatments are limited due to a lack of knowledge about its causes. A new study from the Forsyth Institute is helping to shed light on what happens in the development and the life cycle of the disease. This study is one of the first to define the immune-regulatory mechanisms operating in Sjögren's syndrome and provides a new foundation for fighting the disease. Two specific proteins in the body, programmed death-ligand 1 (PD-L1) along with PD1 have been found to work together to suppress both protective immunity and autoimmune responses to prevent organ damage. According to research published in Scientific Reports, scientists at Forsyth led by Dr. Qing Yu have shown that blockade of the PD-L1-PD-1 pathway made the autoimmune response worse and accelerated the development of Sjögren's syndrome. The hallmark symptoms of Sjögren's syndrome are dry mouth and dry eyes. However, the disease also affects many other organs and causes an array of health complications including B cell lymphoma. In this study, the research team investigated the role of PD-L1 in Sjögren's by inhibiting its function in a common disease model (non-obese diabetic mice). They found that PD-L1 hinders the development and onset of the disease. The study, titled, "Endogenous programmed death ligand-1 restrains the development and onset of Sj?gren's syndrome in non-obese diabetic mice," is published on December 14th in Scientific Reports. This study investigated the previously un-explored role of the PD-L1 pathway in Sjögren's syndrome. Using an experimental mouse disease model, Dr. Yu and her colleagues characterized how the pathway serves to impede and limit the autoimmune responses and the pathologic development of this disease. This novel finding is one of the first to define the immune-regulatory mechanisms operating in Sjögren's syndrome, and provides initial foundation and justification for harnessing the immune-inhibitory pathways, such as PD-L1-PD-1, to combat this high-impact autoimmune disease. This research is supported by grants from the National Institutes of Health R01 DE023838, P30 DE020751. Founded in 1910, the Forsyth Institute is the only independent research organization in the United States dedicated to understanding the important connections between oral health and overall wellness. Forsyth scientists are shaping the direction of personalized medicine through pioneering biomedical research and its direct application to new diagnostics, devices and therapies. Forsyth combines its expertise in oral and associated systemic diseases with a relentless drive to ask - and answer - critical questions about how to best alleviate daily health challenges for billions. Forsyth is a not-for-profit organization that is also committed to treating underserved populations in local communities and on a national and global scale. To learn more about Forsyth, visit http://www. .

Jin J.-O.,Forsyth Institute | Kawai T.,Forsyth Institute | Cha S.,University of Florida | Yu Q.,Forsyth Institute
Arthritis and Rheumatism | Year: 2013

Objective Although elevated interleukin-7 (IL-7) levels have been reported in patients with primary Sjögren's syndrome (SS), the role of IL-7 in this disease remains unclear. We undertook this study to characterize the previously unexplored role of IL-7 in the development and onset of primary SS using the C57BL/6.NOD-Aec1Aec2 (B6.NOD-Aec) mouse model, which recapitulates human primary SS. Methods For gain-of-function studies, recombinant IL-7 or control phosphate buffered saline was injected intraperitoneally (IP) into 12-week-old B6.NOD-Aec mice for 8 weeks. For loss-of-function studies, anti-IL-7 receptor α-chain (anti-IL-7Rα) antibody or its isotype control IgG was administered IP into 16-week-old B6.NOD-Aec mice. Salivary flow measurement, histologic and flow cytometric analysis of salivary glands, and serum antinuclear antibody assay were performed to assess various disease parameters. Results Administration of exogenous IL-7 accelerated the development of primary SS, whereas blockade of IL-7Rα signaling almost completely abolished the development of primary SS, based on salivary gland inflammation and apoptosis, autoantibody production, and secretory dysfunction. IL-7 positively regulated interferon-γ (IFNγ)-producing Th1 and CD8+ T cells in the salivary glands without affecting IL-17. Moreover, IL-7 enhanced the expression of CXCR3 ligands in a T cell- and IFNγ-dependent manner. Accordingly, IFNγ induced a human salivary gland epithelial cell line to produce CXCR3 ligands. IL-7 also increased the level of tumor necrosis factor α, another Th1-associated cytokine that can facilitate tissue destruction and inflammation. Conclusion IL-7 plays a pivotal pathogenic role in SS, which is underpinned by an enhanced Th1 response and IFNγ/CXCR3 ligand-mediated lymphocyte infiltration of target organs. These results suggest that targeting the IL-7 pathway may be a potential future strategy for preventing and treating SS. Copyright © 2013 by the American College of Rheumatology.

Nishikawa K.,Aichi Gakuin University | Duncan M.J.,Forsyth Institute
Journal of Bacteriology | Year: 2010

Porphyromonas gingivalis, a Gram-negative oral anaerobe, is strongly associated with chronic adult periodontitis, and it utilizes FimA fimbriae to persistently colonize and evade host defenses in the periodontal crevice. The FimA-related gene cluster (the fim gene cluster) is positively regulated by the FimS-FimR two-component system. In this study, comparative analyses between fimbriate type strain ATCC 33277 and fimbria-deficient strain W83 revealed differences in their fimS loci, which encode FimS histidine kinase. Using a reciprocal gene exchange system, we established that FimS from W83 is malfunctional. Complementation analysis with chimeric fimS constructs revealed that W83 FimS has a defective kinase domain due to a truncated conserved G3 box motif that provides an ATP-binding pocket. The introduction of the functional fimS from 33277 restored the production, but not polymerization, of endogenous FimA subunits in W83. Further analyses with a fimA-exchanged W83 isogenic strain showed that even the fimbria-deficient W83 retains the ability to polymerize FimA from 33277, indicating the assembly of mature FimA by a primary structure-dependent mechanism. It also was shown that the substantial expression of 33277-type FimA fimbriae in the W83 derivative requires the introduction and expression of the functional 33277 fimS. These findings indicate that FimSR is the unique and universal regulatory system that activates the fim gene cluster in a fimA genotype-independent manner. Copyright © 2010, American Society for Microbiology. All Rights Reserved.

Lanske B.,Harvard University | Razzaque M.S.,Forsyth Institute
Kidney International | Year: 2014

Bone-derived fibroblast growth factor-23 (FGF23) plays an important role in systemic phosphate turnover. Increased FGF23 activity results in hypophosphatemic disorders, while reduced activity is linked to hyperphosphatemic disorders. FGF23, together with klotho as co-factor, can activate FGF receptors in its target tissues to exert its functions. However, the molecular regulation of FGF23 synthesis is not clearly defined, and recent studies have found that parathyroid hormone (PTH) can activate the nuclear receptor-associated protein-1 (Nurr1) to induce FGF23 transcription in bone cells.

Rittling S.R.,Forsyth Institute
Expert Reviews in Molecular Medicine | Year: 2011

The secreted phosphorylated protein osteopontin (OPN) is expressed in a variety of tissues and bodily fluids, and is associated with pathologies including tissue injury, infection, autoimmune disease and cancer. Macrophages are ubiquitous, heterogeneous cells that mediate aspects of cell and tissue damage in all these pathologies. Here, the role of OPN in macrophage function is reviewed. OPN is expressed in macrophage cells in multiple pathologies, and the regulation of its expression in these cells has been described in vitro. The protein has been implicated in multiple functions of macrophages, including cytokine expression, expression of inducible nitric oxide synthase, phagocytosis and migration. Indeed, the role of OPN in cells of the macrophage lineage might underlie its physiological role in many pathologies. However, there are numerous instances where the published literature is inconsistent, especially in terms of OPN function in vitro. Although the heterogeneity of OPN and its receptors, or of macrophages themselves, might underlie some of these inconsistencies, it is important to understand the role of OPN in macrophage biology in order to exploit its function therapeutically. Copyright © 2011 Cambridge University Press.

Razzaque M.S.,Forsyth Institute
Archives of Biochemistry and Biophysics | Year: 2014

An adequate phosphate balance is essential for the maintenance of skeletal growth, development and function. It is also crucial in basic cellular functions, ranging from cell signaling to energy metabolism. Bone-derived fibroblast growth factor 23 (FGF23), through activating FGF receptor system, plays an important role in the systemic regulation of phosphate metabolism. Under physiological conditions, FGF23 exerts serum phosphate-lowering effects by inducing urinary phosphate excretion. Increased FGF23 activities are associated with hypophosphatemic diseases (i.e., rickets/osteomalacia), while reduced FGF23 activity are linked to hyperphosphatemic diseases (i.e., tumoral calcinosis). Unlike most of the FGF family members, FGF23 needs klotho, as a co-factor to activate its receptor system. In vivo studies have convincingly demonstrated that, in absence of klotho, FGF23 is unable to influence systemic phosphate metabolism. Available information suggests that interactions of FGF23, klotho, and FGFRs regulate renal phosphate metabolism by suppressing sodium-phosphate transporters in the proximal tubular epithelial cells. This article briefly summarizes how bone-kidney communication contributes to physiologic phosphate balance. © 2014 Elsevier Inc. All rights reserved.

Jin J.-O.,Forsyth Institute | Han X.,Forsyth Institute | Yu Q.,Forsyth Institute
Journal of Autoimmunity | Year: 2013

Compared with its pro-inflammatory function, the mechanisms underlying the anti-inflammatory effect of IL-6 are poorly understood. IL-6 can cooperate with TGF-β to induce IL-10 production in Th17 cells in vitro. However, the effect of IL-6 on generation of Tr1 cells and the in vivo importance of this effect are mostly uncharacterized. In this study, we showed that in vitro, IL-6 can induce the generation of IL-10-producing Tr1 cells from naïve CD4 T cells, independently of IL-27 and TGF-β. IL-6 induces IL-21 production in CD4 T cells and IL-10-inducing effect of IL-6 requires both IL-21 and IL-2. Although IL-6 cannot induce IL-10 production in CD8 T cells in a cell-autonomous manner, it can do so indirectly through promoting CD4 T cell IL-21 production. The IL-10-producing T cells induced by IL-6 have phenotypic, genetic and functional traits of Tr1 cells and can suppress LPS-induced in vivo inflammatory response in an IL-10-dependent fashion. Blockade of IL-6 in two autoimmune inflammation models, induced respectively by anti-CD3 antibody or Treg-depletion, led to reduction in IL-10-producing T cells and exacerbated inflammation of lung and intestine. Thus, we delineated critical pathways involved in IL-6-induced generation of Tr1 cells and demonstrated the importance of this event in restraining autoimmune tissue inflammation. © 2012 Elsevier Ltd.

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