MOUSE MODEL OF LYME BORRELIOSIS

Summary

Principal Investigator: S W Barthold
Affiliation: University of California
Country: USA
Abstract: DESCRIPTION (Adapted from the applicant's abstract): Human Lyme disease symptoms are inexplicably ephemeral, with spontaneous resolution and episodic recurrences during the course of persistent infection with Borrelia burgdorferi. The investigators have developed a mouse model for human Lyme disease in which mice develop heart and joint disease that undergo spontaneous resolution and episodic recurrence during the course of persistent infection. Immune serum from infected mice, when passively transferred, will protect naive mice against challenge inoculation, as well as selectively induce arthritis resolution in mice with ongoing infection. Compartmentalization of activity to serum facilitates the search for B. burgdorferi antigens responsible for eliciting host immune responses involved in arthritis resolution. They will screen a genomic expression library with immune serum, as well as with monoclonal antibodies generated from infected mice. Monoclonal antibodies will be tested for arthritis-resolving activity in an infant mouse bioassay, and arthritis-resolving monoclonals will be used to directly incriminate the responsible antigen in the expression library. Clones with genes of interest will be sequenced and expressed as recombinant proteins and antisera to recombinant proteins generated. They will then modify the course of infection and arthritis in infected, immunodeficient mice by passive immunization with specific antisera; in infected, immunocompetent mice by active immunization with specific proteins; and in infected, transgenic mice that are immunologically tolerant to the proteins of interest. These studies will be based on the N40 strain of B. burgdorferi. They will then evaluate the specificity of arthritis-resolving antigens/antibodies by examining the effects of antisera against specific proteins of interest in mice infected with homologous or heterologous strains of B. burgdorferi. They will examine the specificity of arthritis-resolving immunity among selected B. burgdorferi sensu stricto, B. afzelii, and B. garinii isolates that are cloned and mouse-adapted. They will also examine the specificity of arthritis-resolving immunity among different B. burgdorferi sensu stricto isolates, selecting members of branches of the B. burgdorferi dendrogram. These studies, for the first time, will investigate antigens involved in disease expression and persistent infection. They offer the potential for development of a therapeutic vaccine for Lyme disease and development of a model for chronic arthritis.
Funding Period: 1988-07-01 - 2002-01-31
more information: NIH RePORT

Top Publications

  1. pmc Resurgence of persisting non-cultivable Borrelia burgdorferi following antibiotic treatment in mice
    Emir Hodzic
    Center for Comparative Medicine, Schools of Medicine and Veterinary Medicine, University of California Davis, Davis, California, United States of America
    PLoS ONE 9:e86907. 2014
  2. pmc Assessment of transcriptional activity of Borrelia burgdorferi and host cytokine genes during early and late infection in a mouse model
    Emir Hodzic
    1 Center for Comparative Medicine, Schools of Veterinary Medicine and Medicine, University of California at Davis, Davis, California
    Vector Borne Zoonotic Dis 13:694-711. 2013
  3. pmc Dynamics of connective-tissue localization during chronic Borrelia burgdorferi infection
    Denise M Imai
    Center for Comparative Medicine, School of Veterinary Medicine, University of California, Davis, CA 95616, USA
    Lab Invest 93:900-10. 2013
  4. pmc Influence of arthritis-related protein (BBF01) on infectivity of Borrelia burgdorferi B31
    Denise Imai
    Center for Comparative Medicine, Schools of Veterinary Medicine and Medicine, University of California, One Shields Avenue, Davis, CA 95616, USA
    BMC Microbiol 13:100. 2013
  5. pmc The early dissemination defect attributed to disruption of decorin-binding proteins is abolished in chronic murine Lyme borreliosis
    Denise M Imai
    Center for Comparative Medicine, Schools of Medicine and Veterinary Medicine, University of California at Davis, Davis, California, USA
    Infect Immun 81:1663-73. 2013
  6. pmc Comparative molecular analyses of Borrelia burgdorferi sensu stricto strains B31 and N40D10/E9 and determination of their pathogenicity
    Kamfai Chan
    Department of Microbiology and Molecular Genetics, University of Medicine and Dentistry of New Jersey, New Jersey Medical School, 225 Warren Street, Newark, NJ 07103 3535, USA
    BMC Microbiol 12:157. 2012
  7. pmc Persistence of Borrelia burgdorferi in rhesus macaques following antibiotic treatment of disseminated infection
    Monica E Embers
    Divisions of Bacteriology and Parasitology, Tulane National Primate Research Center, Tulane University Health Sciences Center, Covington, Louisiana, United States of America
    PLoS ONE 7:e29914. 2012
  8. pmc Lymphoadenopathy during lyme borreliosis is caused by spirochete migration-induced specific B cell activation
    Stefan S Tunev
    Center for Comparative Medicine, University of California Davis, Davis, California, United States of America
    PLoS Pathog 7:e1002066. 2011
  9. ncbi Lyme neuroborreliosis in 2 horses
    D M Imai
    Center of Comparative Medicine, University of California, Davis, One Shields Avenue, Davis, CA 95616, USA
    Vet Pathol 48:1151-7. 2011
  10. pmc Ineffectiveness of tigecycline against persistent Borrelia burgdorferi
    Stephen W Barthold
    Center for Comparative Medicine, School of Medicine, University of California at Davis, One Shields Avenue, Davis, CA 95616, USA
    Antimicrob Agents Chemother 54:643-51. 2010

Scientific Experts

  • S W Barthold
  • N Baumgarth
  • Monica E Embers
  • Emir Hodzic
  • Sunlian Feng
  • Denise M Imai
  • Kevin Holden
  • Denise Imai
  • Kamfai Chan
  • D M Imai
  • Stefan S Tunev
  • Keith O Strother
  • Kimberly J Freet
  • Eric M Velazquez
  • Kim Olsen
  • D Scott Samuels
  • Mehwish Awan
  • Nikhat Parveen
  • Christine J Hastey
  • J M Johnston
  • B Daft
  • K J Olsen
  • E Hodzic
  • B C Barr
  • S Feng
  • J J Bertone
  • Aravinda M de Silva
  • Rance B Lefebvre
  • Kim J Freet
  • Stefan Tunev

Detail Information

Publications15

  1. pmc Resurgence of persisting non-cultivable Borrelia burgdorferi following antibiotic treatment in mice
    Emir Hodzic
    Center for Comparative Medicine, Schools of Medicine and Veterinary Medicine, University of California Davis, Davis, California, United States of America
    PLoS ONE 9:e86907. 2014
    ....
  2. pmc Assessment of transcriptional activity of Borrelia burgdorferi and host cytokine genes during early and late infection in a mouse model
    Emir Hodzic
    1 Center for Comparative Medicine, Schools of Veterinary Medicine and Medicine, University of California at Davis, Davis, California
    Vector Borne Zoonotic Dis 13:694-711. 2013
    ..LDA represents a valuable approach for sensitive and quantitative gene transcription profiling and for understanding Lyme borreliosis...
  3. pmc Dynamics of connective-tissue localization during chronic Borrelia burgdorferi infection
    Denise M Imai
    Center for Comparative Medicine, School of Veterinary Medicine, University of California, Davis, CA 95616, USA
    Lab Invest 93:900-10. 2013
    ..These findings indicate that the specificity of B. burgdorferi tissue localization during chronic infection is determined by decorin, driven by the borrelia-specific antibody response, and fluctuates with the antibody response. ..
  4. pmc Influence of arthritis-related protein (BBF01) on infectivity of Borrelia burgdorferi B31
    Denise Imai
    Center for Comparative Medicine, Schools of Veterinary Medicine and Medicine, University of California, One Shields Avenue, Davis, CA 95616, USA
    BMC Microbiol 13:100. 2013
    ..burgdorferi s.s. isolates, has been shown to be antigenic in humans with Lyme borreliosis, and a target for antibody-mediated disease resolution in the mouse model...
  5. pmc The early dissemination defect attributed to disruption of decorin-binding proteins is abolished in chronic murine Lyme borreliosis
    Denise M Imai
    Center for Comparative Medicine, Schools of Medicine and Veterinary Medicine, University of California at Davis, Davis, California, USA
    Infect Immun 81:1663-73. 2013
    ..Thus, the results indicated that deficiency of DbpA/B allows the acquired immune response to restrict early dissemination of spirochetes, which appears to be at least partially mediated through the lymphatic system...
  6. pmc Comparative molecular analyses of Borrelia burgdorferi sensu stricto strains B31 and N40D10/E9 and determination of their pathogenicity
    Kamfai Chan
    Department of Microbiology and Molecular Genetics, University of Medicine and Dentistry of New Jersey, New Jersey Medical School, 225 Warren Street, Newark, NJ 07103 3535, USA
    BMC Microbiol 12:157. 2012
    ..However, the presence of several known virulence factors in N40 has not been investigated. This is the first comprehensive study that compared these two strains both in vitro and using the mouse model of infection...
  7. pmc Persistence of Borrelia burgdorferi in rhesus macaques following antibiotic treatment of disseminated infection
    Monica E Embers
    Divisions of Bacteriology and Parasitology, Tulane National Primate Research Center, Tulane University Health Sciences Center, Covington, Louisiana, United States of America
    PLoS ONE 7:e29914. 2012
    ..This finding raises important questions about the pathogenicity of antibiotic-tolerant persisters and whether or not they can contribute to symptoms post-treatment...
  8. pmc Lymphoadenopathy during lyme borreliosis is caused by spirochete migration-induced specific B cell activation
    Stefan S Tunev
    Center for Comparative Medicine, University of California Davis, Davis, California, United States of America
    PLoS Pathog 7:e1002066. 2011
    ..Together, these findings suggest a novel evasion strategy for B. burgdorferi: subversion of the quality of a strongly induced, potentially protective borrelia-specific antibody response via B. burdorferi's accumulation in lymph nodes...
  9. ncbi Lyme neuroborreliosis in 2 horses
    D M Imai
    Center of Comparative Medicine, University of California, Davis, One Shields Avenue, Davis, CA 95616, USA
    Vet Pathol 48:1151-7. 2011
    ..In both horses, spirochetes were visualized in affected tissues with Steiner silver impregnation and by immunohistochemistry, predominantly within the dense collagenous tissue of the dura mater and leptomeninges...
  10. pmc Ineffectiveness of tigecycline against persistent Borrelia burgdorferi
    Stephen W Barthold
    Center for Comparative Medicine, School of Medicine, University of California at Davis, One Shields Avenue, Davis, CA 95616, USA
    Antimicrob Agents Chemother 54:643-51. 2010
    ..burgdorferi genes. These results extended previous studies with ceftriaxone, indicating that antibiotic treatment is unable to clear persisting spirochetes, which remain viable and infectious, but are nondividing or slowly dividing...
  11. pmc Persistence of Borrelia burgdorferi following antibiotic treatment in mice
    Emir Hodzic
    Center for Comparative Medicine, School of Medicine, University of California at Davis, One Shields Avenue, Davis, CA 95616, USA
    Antimicrob Agents Chemother 52:1728-36. 2008
    The effectiveness of antibiotic treatment was examined in a mouse model of Lyme borreliosis. Mice were treated with ceftriaxone or saline solution for 1 month, commencing during the early (3 weeks) or chronic (4 months) stages of ..
  12. pmc Infection of mice with lyme disease spirochetes constitutively producing outer surface proteins a and B
    Keith O Strother
    Department of Microbiology and Immunology, University of Chapel Hill, Chapel Hill, NC 27599, USA
    Infect Immun 75:2786-94. 2007
    ..We conclude that spirochetes producing OspA and B from the flaB promoter in immunocompetent mice stimulate an immune response that clear the bacteria without any signs of disease development in the mice...
  13. pmc Antibody-mediated disease remission in the mouse model of lyme borreliosis
    Stephen W Barthold
    Center for Comparative Medicine, School of Medicine, University of California at Davis, One Shields Avenue, Davis, California 95616, USA
    Infect Immun 74:4817-25. 2006
    In the mouse model of Lyme borreliosis, the host immune response during infection with Borrelia burgdorferi results in the remission of carditis and arthritis, as well as global reduction of spirochete numbers in tissues, without ..
  14. pmc Coinfection with Anaplasma phagocytophilum alters Borrelia burgdorferi population distribution in C3H/HeN mice
    Kevin Holden
    Center for Comparative Medicine, University of California at Davis, One Shields Avenue, Davis, CA 95616, USA
    Infect Immun 73:3440-4. 2005
    ..burgdorferi modulates pathogen burden and host antibody responses. This may be explained by the ability of A. phagocytophilum to functionally impair neutrophils, important cells in the early defense against B. burgdorferi infection...
  15. pmc Immunoglobulin-regulated expression of Borrelia burgdorferi outer surface protein A in vivo
    Emir Hodzic
    Center for Comparative Medicine, University of California at Davis, One Shields Avenue, Davis, CA 95616, USA
    Infect Immun 73:3313-21. 2005
    ..Collectively, our results indicate that ospA mRNA transcription in the host is regulated by nonspecific immunoglobulin, which may be a natural antibody...