Borrelia burgdorferi: invasion and chronicity

Summary

Principal Investigator: Jorge Benach
Affiliation: State University of New York
Country: USA
Abstract: This project has focused on investigations regarding the invasiveness of both Borrelia burgdorferi and of Borrelia of relapsing fever. There is an intimate and also required association of Borrelia with the mammalian plasminogen activation system (PAS). The interaction of Borrelia with the PAS provides the spirochetes with borrowed proteolytic activity which in turn enhance invasiveness. The interaction goes even further to include the utilization of the cellular aspects of the PAS to also promote invasiveness and a reduction in inflammation. Studies that demonstrate that Borrelia interacts with each of the PAS components were completed, and documentation was provided for changes in gene expression when Borrelia are stimulated by blood. This project, will consider changes that occur in Borrelia gene expression as a result of contact with blood that result in invasion. In the previous period of this project, we obtained compelling evidence that the biogenesis of critical proteins such as OspC and DbpA were regulated during blood induction by an upregulated Lon-1 protease. The first Specific Aim will study a mechanism whereby blood-induced gene products contribute to invasion by B. burgdorferi. Through microarray experiments, blood markedly induced the upregulation of ospC, dbpA, p35, and lon-1 (among 154 other genes). Lon-1 is an ATP-dependent protease that degrades damaged, senescent, or misfolded proteins. In a lon-1 Borrelia knockout, the levels of OspC, DbpA, and P35 protein were reduced following stimulation with blood even though transcription of these proteins remained elevated. A lon-1 knockout showed an impaired infectivity phenotype and was particularly deficient in invading and colonizing the skin. The possibility that the Lon-1 of Borrelia may have both proteolytic and chaperone functions in the biogenesis of proteins required for invasion will be tested by biochemical (using soluble recombinant wild type and mutant Lon-1) and genetic approaches (using lon-1 knockout and lon-1 complemented strains of infectious B. burgdorferi). Mouse experiments are planned to test the hypothesis that Lon-1 is important in the production of proteins that could be considered to be virulence factors. Since OspC has been shown to be essential for infection of mammals, the hypothesis is that interaction of Lon-1 with OspC (and others to be identified in Specific Aim II) leads to changes in invasion. In Specific Aim II, additional Borrelia responses to stimulation with blood and that lead to invasion will be identified. In this part of the project, the genes associated with the wild type lon-1 and lon-1 mutant (as well as complemented mutants) under stimulation with blood will be identified. Identification of the blood induced regulon will be achieved by proteomic and genomic approaches.
Funding Period: ----------------1990 - ---------------2012-
more information: NIH RePORT

Top Publications

  1. ncbi Reciprocal upregulation of urokinase plasminogen activator and its inhibitor, PAI-2, by Borrelia burgdorferi affects bacterial penetration and host-inflammatory response
    Woldeab B Haile
    Center for Infectious Diseases, Department of Molecular Genetics and Microbiology, Stony Brook University, Stony Brook, NY 11794 5120, USA
    Cell Microbiol 8:1349-60. 2006
  2. pmc Lipid exchange between Borrelia burgdorferi and host cells
    Jameson T Crowley
    Department of Molecular Genetics and Microbiology, Center for Infectious Diseases, Stony Brook University, Stony Brook, New York, USA
    PLoS Pathog 9:e1003109. 2013
  3. pmc Proving lipid rafts exist: membrane domains in the prokaryote Borrelia burgdorferi have the same properties as eukaryotic lipid rafts
    Timothy J LaRocca
    Department of Molecular Genetics and Microbiology, Stony Brook University, Stony Brook, New York, United States of America
    PLoS Pathog 9:e1003353. 2013
  4. ncbi The loss and gain of marginal zone and peritoneal B cells is different in response to relapsing fever and Lyme disease Borrelia
    Susan Malkiel
    Center for Infectious Diseases, Department of Molecular Genetics and Microbiology, Stony Brook University, Stony Brook, NY 11794, USA
    J Immunol 182:498-506. 2009
  5. pmc Evidence that two ATP-dependent (Lon) proteases in Borrelia burgdorferi serve different functions
    James L Coleman
    State of New York Department of Health, Stony Brook University, Stony Brook, New York, United States of America
    PLoS Pathog 5:e1000676. 2009
  6. pmc Phylogenetic analysis of a virulent Borrelia species isolated from patients with relapsing fever
    A Toledo
    Department of Molecular Genetics and Microbiology, Center for Infectious Diseases, Stony Brook University, Stony Brook, NY 11794 5120, USA
    J Clin Microbiol 48:2484-9. 2010
  7. pmc Cholesterol lipids of Borrelia burgdorferi form lipid rafts and are required for the bactericidal activity of a complement-independent antibody
    Timothy J LaRocca
    Department of Molecular Genetics and Microbiology, and Center for Infectious Diseases, Stony Brook University, Stony Brook, NY 11794, USA
    Cell Host Microbe 8:331-42. 2010
  8. pmc The enolase of Borrelia burgdorferi is a plasminogen receptor released in outer membrane vesicles
    A Toledo
    Department of Molecular Genetics and Microbiology, Center for Infectious Diseases, Stony Brook University, Stony Brook, New York, USA
    Infect Immun 80:359-68. 2012

Scientific Experts

  • J L Coleman
  • Timothy J LaRocca
  • Jorge L Benach
  • A Toledo
  • Erwin London
  • Jameson T Crowley
  • Priyadarshini Pathak
  • J L Benach
  • Susan Malkiel
  • Woldeab B Haile
  • John R Silvius
  • Alvaro Toledo
  • Alvaro M Toledo
  • Salvatore Chiantia
  • C J Kuhlow
  • J T Crowley
  • Jordi Benach
  • Brian J Cusack
  • P Anda
  • R Escudero
  • C Larsson
  • S Bergstrom
  • Juan C Garcia-Monco
  • Patricio Mena
  • Christopher J Kuhlow

Detail Information

Publications8

  1. ncbi Reciprocal upregulation of urokinase plasminogen activator and its inhibitor, PAI-2, by Borrelia burgdorferi affects bacterial penetration and host-inflammatory response
    Woldeab B Haile
    Center for Infectious Diseases, Department of Molecular Genetics and Microbiology, Stony Brook University, Stony Brook, NY 11794 5120, USA
    Cell Microbiol 8:1349-60. 2006
    ..These results show that the PAS plays a twofold role in the pathogenesis of B. burgdorferi infection, both by enhancing bacterial dissemination and by diminishing host-cell inflammatory migration...
  2. pmc Lipid exchange between Borrelia burgdorferi and host cells
    Jameson T Crowley
    Department of Molecular Genetics and Microbiology, Center for Infectious Diseases, Stony Brook University, Stony Brook, New York, USA
    PLoS Pathog 9:e1003109. 2013
    ..Thus, two-way lipid exchange between spirochetes and host cells can occur. This lipid exchange could be an important process that contributes to the pathogenesis of Lyme disease...
  3. pmc Proving lipid rafts exist: membrane domains in the prokaryote Borrelia burgdorferi have the same properties as eukaryotic lipid rafts
    Timothy J LaRocca
    Department of Molecular Genetics and Microbiology, Stony Brook University, Stony Brook, New York, United States of America
    PLoS Pathog 9:e1003353. 2013
    ..These findings provide compelling evidence for the existence of lipid rafts and show that the same principles of lipid raft formation apply to prokaryotes and eukaryotes despite marked differences in their lipid compositions...
  4. ncbi The loss and gain of marginal zone and peritoneal B cells is different in response to relapsing fever and Lyme disease Borrelia
    Susan Malkiel
    Center for Infectious Diseases, Department of Molecular Genetics and Microbiology, Stony Brook University, Stony Brook, NY 11794, USA
    J Immunol 182:498-506. 2009
    ..Our data demonstrate that different Borrelia can activate the same B cell subsets in distinct ways and they each elicit a complex interplay of MZ and multiple peritoneal B cell subsets in the early response to infection...
  5. pmc Evidence that two ATP-dependent (Lon) proteases in Borrelia burgdorferi serve different functions
    James L Coleman
    State of New York Department of Health, Stony Brook University, Stony Brook, New York, United States of America
    PLoS Pathog 5:e1000676. 2009
    ..Lon-1, by virtue of its blood induction, and as a unique feature of the Borreliae, may be important in host adaptation from the arthropod to a warm-blooded host...
  6. pmc Phylogenetic analysis of a virulent Borrelia species isolated from patients with relapsing fever
    A Toledo
    Department of Molecular Genetics and Microbiology, Center for Infectious Diseases, Stony Brook University, Stony Brook, NY 11794 5120, USA
    J Clin Microbiol 48:2484-9. 2010
    ..Therefore, we propose to use strain SP1, isolated from a relapsing fever patient in 1994 in southern Spain, as the type strain for B. hispanica...
  7. pmc Cholesterol lipids of Borrelia burgdorferi form lipid rafts and are required for the bactericidal activity of a complement-independent antibody
    Timothy J LaRocca
    Department of Molecular Genetics and Microbiology, and Center for Infectious Diseases, Stony Brook University, Stony Brook, NY 11794, USA
    Cell Host Microbe 8:331-42. 2010
    ..burgdorferi lipid raft organization may have significant implications in the transmission cycle of the spirochetes which are exposed to a range of temperatures...
  8. pmc The enolase of Borrelia burgdorferi is a plasminogen receptor released in outer membrane vesicles
    A Toledo
    Department of Molecular Genetics and Microbiology, Center for Infectious Diseases, Stony Brook University, Stony Brook, New York, USA
    Infect Immun 80:359-68. 2012
    ..Thus, this immunogenic plasminogen receptor released in outer membrane vesicles could be responsible for external proteolysis in the pericellular environment and have roles in nutrition and in enhancing dissemination...