Role of Obesity in Infection

Summary

Principal Investigator: S Amar
Affiliation: Boston University
Country: USA
Abstract: Obesity is a global problem affecting over 1 billion adults and 17.6 million children under 5 years of age. Since 1980, 3-fold increases in obesity have been reported worldwide. Obesity poses an increased risk of developing many secondary conditions, including atherosclerosis, diabetes, non-alcoholic fatty liver disease, periodontal disease, certain cancers, and asthma. Given the disease burden associated with obesity, a better understanding of the local and systemic complications arising from this condition and effective modalities for its treatment seem critical and timely. Obesity is now viewed to result in a dysregulation of the innate immune system leading to an attenuated systemic inflammation. However, a precise understanding of the molecular mechanisms that underlie this immune-metabolic linkage is lacking, but will be critically important for rational intervention. Intriguingly, and cogent to this proposal, recent epidemiological studies have linked obesity to periodontal disease. The possible causal relationship(s) between obesity and periodontitis, and the underlying biological mechanisms warrant a robust investigation. Provocatively, our preliminary data show that when wild-type mice are fed a high fat diet for 16 weeks - as a model for induced obesity they display a dramatic and reproducibly attenuated proinflammatory cytokine profile in a Porphyromonas gingivalis (P.g)-dependent model of periodontal disease, in contrast to lean mice fed a standard chow diet. Furthermore, in this model, obese animals experience greater periodontal bone loss compared to lean ones. Finally, we have found that obesity impairs the mechanisms associated with host clearance of P.g. from the oral environment. Based on these data, and data presented in this proposal, we hypothesize that diet-induced obesity (DIO) alters the innate immune response to P.g, such that macrophages mount an attenuated anti-bacterial response, which leads to aggravated periodontal bone loss. A better understanding of the link between obesity and innate immune response will likely have profound implications for the design of new therapies and modalities aimed at reducing clinical sequelae associated with obesity. In this application, we propose the following Specific Aims: Aim 1 will determine the effect of DIO on the severity of P.g-associated experimental periodontitis. Aim 2 will establish the functional significance of chromatin modification and TLR signaling pathways uniquely affected by DIO in response to P.g infection. Aim 3 will determine the effect of TLR2 deficiency on DIO in our murine periodontitis model. Our approach should provide novel and crucial data that will deepen our understanding of the pathway-specific mechanisms involved in the diet-induced regulation of host innate immune response to pathogens. The characterization of diet-specific pathways may eventually allow the design of new classes of compounds to treat obesity-related diseases. NARRATIVE: Our approach will test the hypothesis that diet-induced obesity alters the immune response to Porphyromonas gingivalis which leads to an aggravated alveolar bone loss in obese animals. The results of these studies should provide novel and crucial data that will deepen our understanding of the pathway-specific mechanisms involved in the diet- induced regulation of host innate immune response to pathogens. New knowledge gained from the proposed studies will likely have profound implications for the design of new therapies and modalities aimed at reducing clinical sequelae associated with obesity.
Funding Period: ----------------2004 - ---------------2013-
more information: NIH RePORT

Top Publications

  1. pmc Identification of proteins differentially expressed in human monocytes exposed to Porphyromonas gingivalis and its purified components by high-throughput immunoblotting
    Qingde Zhou
    Department of Periodontology and Oral Biology, School of Dental Medicine, Boston University Medical Center, 700 Albany Street W 201E, Boston, MA 02118, USA
    Infect Immun 74:1204-14. 2006
  2. doi An application of monotone functions decomposition to the reconstruction of gene regulatory networks
    H Chang
    Dept of Mechanical Engineering, Boston University, Boston, MA 02215, USA
    Conf Proc IEEE Eng Med Biol Soc 2011:2430-3. 2011
  3. pmc Bioinformatics analysis of macrophages exposed to Porphyromonas gingivalis: implications in acute vs. chronic infections
    Wen Han Yu
    Bioinformatics Graduate Program, Boston University, Boston, Massachusetts, United States of America
    PLoS ONE 5:e15613. 2010
  4. pmc Diet-induced obesity in mice causes changes in immune responses and bone loss manifested by bacterial challenge
    Salomon Amar
    Department of Periodontology and Oral Biology, School of Dental Medicine, School of Medicine, Boston University, Boston, MA 02118, USA
    Proc Natl Acad Sci U S A 104:20466-71. 2007
  5. pmc Lung lining fluid glutathione attenuates IL-13-induced asthma
    Matthew H Lowry
    The Pulmonary Center, Boston University School of Medicine, 715 Albany Street, Boston, MA 02118, USA
    Am J Respir Cell Mol Biol 38:509-16. 2008
  6. ncbi Identification of signaling pathways in macrophage exposed to Porphyromonas gingivalis or to its purified cell wall components
    Qingde Zhou
    Department of Periodontology and Oral Biology, School of Dental Medicine, Boston University, Boston, MA 02118, USA
    J Immunol 179:7777-90. 2007
  7. ncbi Inhibition of SFRP1 reduces severity of periodontitis
    C H Li
    Department of Periodontology and Oral Biology, Goldman School of Dental Medicine, Boston University, Boston, MA 02118, USA
    J Dent Res 86:873-7. 2007
  8. pmc Immunization enhances inflammation and tissue destruction in response to Porphyromonas gingivalis
    Cataldo W Leone
    Department of Periodontology and Oral Biology, Boston University Goldman School of Dental Medicine, 700 Albany Street, W 201, Boston, MA 02118, USA
    Infect Immun 74:2286-92. 2006
  9. pmc Role of secreted frizzled-related protein 1 (SFRP1) in wound healing
    C H Li
    Department of Periodontology and Oral Biology, Goldman School of Dental Medicine, Boston University, Boston, MA 02118, USA
    J Dent Res 85:374-8. 2006
  10. pmc Partial restoration of macrophage alteration from diet-induced obesity in response to Porphyromonas gingivalis infection
    Guilhem Richard
    Department of Bioinformatics, Boston University, Boston, Massachusetts, United States of America
    PLoS ONE 8:e70320. 2013

Scientific Experts

  • S Amar
  • Qingde Zhou
  • Guilhem Richard
  • C H Li
  • Calin Belta
  • H Chang
  • Susan E Leeman
  • Wen Han Yu
  • Varun Mazumdar
  • Matthew H Lowry
  • Chung Hsing Li
  • Julian A Saba
  • Cataldo W Leone
  • Niraj Trivedi
  • A Agung Julius
  • G Richard
  • A A Julius
  • C Belta
  • Han Hu
  • Yu Xia
  • Evan S Snitkin
  • Daniel Segrè
  • Pamela Johnson
  • Rebecca P Hughey
  • Edgar C Lucey
  • Martin Joyce-Brady
  • Thomas N Wight
  • Brian P McAllister
  • Kathleen Braun
  • William W Cruikshank
  • Lou Ann S Brown
  • Jyh Chang Jean
  • Catherine E Costello
  • Mark E McComb
  • Donna L Potts
  • David Kuo
  • Dana T Graves
  • Tesfahun Desta
  • Julia Yang
  • Haneen Bokhadhoor
  • Michelle F Siqueira

Detail Information

Publications17

  1. pmc Identification of proteins differentially expressed in human monocytes exposed to Porphyromonas gingivalis and its purified components by high-throughput immunoblotting
    Qingde Zhou
    Department of Periodontology and Oral Biology, School of Dental Medicine, Boston University Medical Center, 700 Albany Street W 201E, Boston, MA 02118, USA
    Infect Immun 74:1204-14. 2006
    ..gingivalis, LPS, and FimA. These differential changes are interpreted as preferential signal pathway activation in host immune/inflammatory responses to P. gingivalis infection...
  2. doi An application of monotone functions decomposition to the reconstruction of gene regulatory networks
    H Chang
    Dept of Mechanical Engineering, Boston University, Boston, MA 02215, USA
    Conf Proc IEEE Eng Med Biol Soc 2011:2430-3. 2011
    ..Our validation shows that our model predicts the expression levels of the genes involved in the network with good accuracy...
  3. pmc Bioinformatics analysis of macrophages exposed to Porphyromonas gingivalis: implications in acute vs. chronic infections
    Wen Han Yu
    Bioinformatics Graduate Program, Boston University, Boston, Massachusetts, United States of America
    PLoS ONE 5:e15613. 2010
    ..Microarray data from treated macrophages or control cells were analyzed to define molecular signatures. Changes in genes identified in relevant pathways were validated by RT-PCR...
  4. pmc Diet-induced obesity in mice causes changes in immune responses and bone loss manifested by bacterial challenge
    Salomon Amar
    Department of Periodontology and Oral Biology, School of Dental Medicine, School of Medicine, Boston University, Boston, MA 02118, USA
    Proc Natl Acad Sci U S A 104:20466-71. 2007
    ..gingivalis infection and suggest that this immune dysregulation participates in the increased alveolar bone loss after bacterial infection observed in mice with DIO...
  5. pmc Lung lining fluid glutathione attenuates IL-13-induced asthma
    Matthew H Lowry
    The Pulmonary Center, Boston University School of Medicine, 715 Albany Street, Boston, MA 02118, USA
    Am J Respir Cell Mol Biol 38:509-16. 2008
    ..Inhibiting GGT activity in lung lining fluid may represent a novel therapeutic approach for preventing and treating asthma...
  6. ncbi Identification of signaling pathways in macrophage exposed to Porphyromonas gingivalis or to its purified cell wall components
    Qingde Zhou
    Department of Periodontology and Oral Biology, School of Dental Medicine, Boston University, Boston, MA 02118, USA
    J Immunol 179:7777-90. 2007
    ..gingivalis LPS uniquely induces ISRE-containing genes, which requires IFNalphabetaR signaling involving IRF7, KLF4, and pY701 STAT1...
  7. ncbi Inhibition of SFRP1 reduces severity of periodontitis
    C H Li
    Department of Periodontology and Oral Biology, Goldman School of Dental Medicine, Boston University, Boston, MA 02118, USA
    J Dent Res 86:873-7. 2007
    ..The results of our studies suggest that SFRP1 may be involved in the development of periodontitis, since inhibiting SFRP1 resulted in reduced periodontal breakdown...
  8. pmc Immunization enhances inflammation and tissue destruction in response to Porphyromonas gingivalis
    Cataldo W Leone
    Department of Periodontology and Oral Biology, Boston University Goldman School of Dental Medicine, 700 Albany Street, W 201, Boston, MA 02118, USA
    Infect Immun 74:2286-92. 2006
    ..gingivalis increases the inflammatory and destructive responses which occur in part through up-regulating the innate immune response and enhancing osteoclastogenesis and fibroblast apoptosis...
  9. pmc Role of secreted frizzled-related protein 1 (SFRP1) in wound healing
    C H Li
    Department of Periodontology and Oral Biology, Goldman School of Dental Medicine, Boston University, Boston, MA 02118, USA
    J Dent Res 85:374-8. 2006
    ..Analysis of the present data suggests that SFRP1 may be partly responsible for the poorer healing performance of the palatal wounds compared with dermal wounds. Blocking SFRP1 results in improvement of palatal healing outcomes...
  10. pmc Partial restoration of macrophage alteration from diet-induced obesity in response to Porphyromonas gingivalis infection
    Guilhem Richard
    Department of Bioinformatics, Boston University, Boston, Massachusetts, United States of America
    PLoS ONE 8:e70320. 2013
    ..gingivalis exposure. These data indicate that thrombospondin 1 and arginase 1 are important bacterial response genes, whose regulation is altered in macrophages from obese mice...
  11. pmc Proteomic mapping of stimulus-specific signaling pathways involved in THP-1 cells exposed to Porphyromonas gingivalis or its purified components
    Julian A Saba
    Department of Periodontology and Oral Biology, Boston University School of Dental Medicine, Boston, Massachusetts 02118, USA
    J Proteome Res 6:2211-21. 2007
    ..These differential changes by the bacteria and its components are interpreted as preferential signal pathway activation in host immune/inflammatory responses to P.g. infection...
  12. ncbi Morphometric, histomorphometric, and microcomputed tomographic analysis of periodontal inflammatory lesions in a murine model
    Chung Hsing Li
    Department of Periodontology and Oral Biology, Goldman School of Dental Medicine, Boston University, Boston, MA, USA
    J Periodontol 78:1120-8. 2007
    ..The aims of this study were to assess periodontal inflammatory lesions after P. gingivalis-induced periodontitis and use this model to compare three approaches for assessing alveolar bone loss...
  13. pmc Signaling mechanisms involved in altered function of macrophages from diet-induced obese mice affect immune responses
    Qingde Zhou
    Department of Periodontology and Oral Biology, School of Dental Medicine, Boston University, Boston, MA 02118, USA
    Proc Natl Acad Sci U S A 106:10740-5. 2009
    ..These findings unveil a link between obesity and innate immunity...
  14. pmc Metabolic network model of a human oral pathogen
    Varun Mazumdar
    Boston University, Bioinformatics Program, Boston, MA 02215, USA
    J Bacteriol 191:74-90. 2009
    ..The current model, which is amenable to further experimental testing and refinements, could prove useful in evaluating the oral microbiome dynamics and in the development of novel biomedical applications...
  15. pmc Signaling mechanisms in the restoration of impaired immune function due to diet-induced obesity
    Qingde Zhou
    Center for Anti Inflammatory Therapeutics, School of Dental Medicine, Boston University, Boston, MA 02118, USA
    Proc Natl Acad Sci U S A 108:2867-72. 2011
    ..Thus, metabolizing FFAs and TNF by moderate daily exercise with dietary control improves innate immune responses to infection in DIO mice via restoration of CTMP and chromatin modification...
  16. pmc Controlling the outcome of the Toll-like receptor signaling pathways
    Guilhem Richard
    Program in Bioinformatics, Boston University, Boston, Massachusetts, United States of America
    PLoS ONE 7:e31341. 2012
    ..We mapped the species of the TLR network to genes in human and mouse, and determined more than 10,000 Essential Gene Sets (EGS). Each EGS provides genes whose deletion suppresses the network's outputs...