Dual Function of VPO1 in Pathogen Recognition and Killing

Summary

Principal Investigator: Guangjie Cheng
Abstract: DESCRIPTION (provided by applicant): Innate immunity is broadly defined as the first line of defense against invading pathogens. Innate immune recognition is classically mediated by the interaction of pattern-recognition receptors (PRRs) and pathogen-associated molecular patterns (PAMPs), triggering serial downstream signaling events;alternatively, a number of enzymes such as lysozyme, digestive enzymes and defensins indiscriminately kill bacteria when the enzyme encounters the microbes. In the latter case, the enzyme does not directly recognize microbes, and the elimination of invading microbes is non-specific. Whether there is a PRR to directly kill invading microorganisms remains to be elucidated. Vascular peroxidase 1 (VPO1) is a newly-discovered mammalian heme-containing peroxidase (hPx). VPO1 is unique among the members of hPx family in that it contains a catalytic domain at its C-terminus and a large N-terminal region including five leucine-rich regions (LRRs) and four immunoglobulin (Ig) C2 type domains. VPO1 is highly expressed in the cardiovascular system, lung, liver, pancreas and spleen, and is secreted into bloodstream at a 1000-fold higher concentration than is MPO. However, its biological function has not been established. The central hypothesis of this proposed research is that VPO1 can recognize and directly kill invading microbes. Our specific aims are to (1) determine whether the LRR and Ig C2 domains of VPO1 bind to PAMPs;(2) determine if the binding of VPO1, via LRR and Ig C2, mediates microbicidal activity via generation of hypohalous acids. The major methods for addressing the aims include molecular cloning and expressing, protein purification, fluorescence polarization technology and surface plasmon resonance technology. Successful completion of this proposal will: (1) provide novel insights into innate immune responses;(2) identify the first mammalian protein with dual functions of pathogen recognition and killing;(3) create a new paradigm in the maintenance of bloodstream sterility by the physiological action of a novel dual function hPx;(4) elucidate the molecular mechanisms of VPO1-mediated pathogen recognition and killing, setting the foundation for the future development of diagnostics and/or therapeutics involving this novel innate immune pathway.
Funding Period: 2012-09-01 - 2014-08-31
more information: NIH RePORT

Top Publications

  1. pmc VPO1 mediates ApoE oxidation and impairs the clearance of plasma lipids
    Youfeng Yang
    Division of Pulmonary, Allergy and Critical Care Medicine, Department of Medicine, University of Alabama at Birmingham, Birmingham, Alabama, United States of America
    PLoS ONE 8:e57571. 2013

Detail Information

Publications1

  1. pmc VPO1 mediates ApoE oxidation and impairs the clearance of plasma lipids
    Youfeng Yang
    Division of Pulmonary, Allergy and Critical Care Medicine, Department of Medicine, University of Alabama at Birmingham, Birmingham, Alabama, United States of America
    PLoS ONE 8:e57571. 2013
    ..and secreted into plasma. Its plasma concentration is three orders of magnitude of that of myeloperoxidase. If VPO1 mediates ApoE oxidation and affects the lipid metabolism remains to be elucidated...

Research Grants30

  1. Endothelial Injury and Repair: CardioPulmonary Vascular Biology COBRE
    SHARON IRENE SMITH ROUNDS; Fiscal Year: 2013
    ..abstract_text> ..
  2. Microbial Pattern Recognition and Signaling by the Adhesion GPCR BAI1
    James E Casanova; Fiscal Year: 2013
    ..abstract_text> ..
  3. A TOLERANCE APPROACH TO XENOTRANSPLANTATION
    David H Sachs; Fiscal Year: 2013
    ..abstract_text> ..
  4. Optimization of HIV vaccines for the induction of cross-reactive antibodies
    Shan Lu; Fiscal Year: 2013
    ..RELEVANCE: To optimize the next generation polyvalent Env HIV vaccine formulations using the multi-gene, polyvalent DNA prime - protein boost technology platform. ..
  5. Translational Analyses of Chronic Aberrant Behavior Across the Life Span
    ISER DELEON; Fiscal Year: 2013
    ..Evidence arising from this multi-site, multi-faceted approach to the treatment of CAB in IDD will make it possible to design better therapeutic individuals with IDD to lead better lives. ..
  6. Transplant Tolerance in Non-Human Primates
    STUART JOHNSTON KNECHTLE; Fiscal Year: 2013
    ..This goal will be accomplished via four interrelated projects and two supporting cores. ..
  7. Genomics for Transplantation: Discovery and Biomarkers
    Daniel R Salomon; Fiscal Year: 2013
    ..Ultimately, we hope to create the genomic tools that will allow physicians to optimize and personalize the safety and efficacy of immunosuppression. ..
  8. University of New Mexico Interdisciplinary HPV Prevention Center
    Cosette Marie Wheeler; Fiscal Year: 2013
    ..abstract_text> ..
  9. Lipid Effector Molecules of Innate Immunity: Antimicrobial Cholesteryl Esters
    Edith Porter; Fiscal Year: 2013
    ..Last, not least, this research may lead to the discovery of novel virulence factors of pathogenic microbes that circumvent host defenses mediated by antimicrobial lipids in the respiratory tract and on other mucosal surfaces. ..
  10. Rocky Mountain Regional Center of Excellence or Biodefense and Emerging Infectiou
    John T Belisle; Fiscal Year: 2013
    ..abstract_text> ..
  11. Pacific NorthWest Regional Center of Excellence (PNWRCE)
    Jay A Nelson; Fiscal Year: 2013
    ..pseudomallei host pathogen response during both the septicemic as well as the intracellular phases of the disease. ..
  12. Southeast Regional Centers of Excellence for Biodefense &Emerging Infectious Di
    Philip Frederick Sparling; Fiscal Year: 2013
    ..SERCEB brings new investigators to the biodefense effort through a combination of educational programs, support of innovative new projects, and the synergistic interactions among its world-class investigators. ..
  13. Duodenal Mucosal Defense Mechanisms
    Jonathan D Kaunitz; Fiscal Year: 2013
    ..Since Duox is hypothesized to control foregut bacterial colonization, the proposed system may bear on several important diseases, such as small intestinal bacteria overgrowth (SIBO), cystic fibrosis, and inflammatory bowel disease. ..
  14. Innate Immune Sensing of Bacterial Sugars
    David M Underhill; Fiscal Year: 2013
    ..In aim three well will explor how the Gram-positive peptidoglycan recycling system can be manipulated to influence signaling by this pathway in immune cells and alter microbial pathogenesis. ..
  15. Northeast Biodefense Center
    W Ian Lipkin; Fiscal Year: 2013
    ..As a Center based in a School of Public Health and a State Department of Health, the NBC has a firm commitment to and practical understanding of Emergency Preparedness. ..
  16. Boosting Innate Immunity Through HIF to Treat Antibiotic-Resistant Infections
    ROBERT ALAN SHALWITZ; Fiscal Year: 2013
    ..Ultimately, HIF-1 immune boosting therapy could find wide application in the treatment of difficult infections complicated by antibiotic resistance or weakened host defense. ..
  17. Inflammatory Caspases in Innate Immunity and Inflammation
    Thirumala Devi Kanneganti; Fiscal Year: 2013
    ....
  18. When Autophagy Meets Phagocytosis
    Jae U Jung; Fiscal Year: 2013
    ..This proposal is highly novel and innovative, and a successful outcome will potentially lead to a paradigm shift in our understanding of host ancient innate immunity and the development of anti-microbe strategies. ..
  19. Role of GSK3 in host inflammation
    David A Scott; Fiscal Year: 2013
    ..Therefore, this project will lay the groundwork for the development of novel approaches to the treatment of periodontitis and other inflammatory diseases and identify therapeutic targets that should be readily translatable. ..
  20. Molecular Analyses and Interventions for Biodefense and Emerging Pathogens
    Olaf Schneewind; Fiscal Year: 2013
    ..Research and training at the GLRCE is governed by a mechanism involving ongoing review of scientific excellence and translational goals, inter-institutional advisory boards and external scientific advisory bodies. ..
  21. New England Regional Center of Excellence in Biodefense and Emerging Infectious D
    Dennis L Kasper; Fiscal Year: 2013
    ..NERCE will also continue its Developmental Projects program and Career Development in Biodefense program in an effort to initiate new research efforts and to attract new investigators to this field. ..
  22. B Cells in Health and Disease
    IGNACIO E SANZ; Fiscal Year: 2013
    ..Finally, and central to this PPG, our results will greatly enhance our ability to design better and safer BCDT therapies and to develop biomarkers of B cell targeted treatments efficacy and safety. ..