We have developed a rabbit Lyme Disease model in which early erythema migrans (EM) lesions and disseminated infection occur and in which complete infection-derived immunity results. The long term - objectives of this study are to determine protective and pathological immune mechanisms operative during the course of rabbit infection with Borrelia burgdorferi (Bb). The rabbit model of Lyme disease provides a unique opportunity to address local and disseminated disease manifestations similar to those in human infection, and to address the cellular and humoral immune mechanisms in infection-derived immunity. Specific and cross-reactive immunity to challenge will be determined utilizing several well-defined strains. The in situ localization and fate of Bb in skin following intradermal challenge will be correlated with the presence and distribution of PMN's, B cells, and T cell subsets both in situ and in peripheral blood. correlations with acquired resistance will also be made with in vitro lymphocytic cell proliferative responses and humoral immune responses including quantitative ELISA and Western blot analysis, passive protection, opsonophagocytosis, complemet-dependent borreliacidal activity, adherence inhibition, and freeze-fracture electron microscopy for the detection of antibody against Bb outer membrane proteins. The rabbit model will also be employed to address the efficacy of Bb challenge following vaccination with OspA, OspB, an avirulent Bb OspA- and OspB-less mutant, and with a recombinant gene product encoding an exported plasmid protein antigen (EppA). The cellular and humoral arms of the immune response as it relates to the development and healing of the EM lesion will also be addressed utilizing the above described procedures. Further, continued persistence, location, and subsequent elimination of the spirochete after EM healing will be determined by specific in situ analysis. Passive protection studies will be conducted with serum obtained at the time of Bb clearance from the skin in order to determine the immune status of these animals. The possibility of exotoxin in EM formation will be determined by injecting rabbits intradermally with concentrated supernatants from in vitro Bb cultures and by the use of filtrates prepared and concentrated from surgically implanted subcutaneous chambers containing Bb. The rabbit model permits the elucidation of those mechanisms that control persistence versus elimination in tissues to which the organism has disseminated. Studies directed toward the elucidation of dermatotropic, arthritogenic, and/or neurotropic strains utilizing several isolates of Bb are proposed and should contribute toward our understanding of chronicity in humans.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Project (R01)
Project #
5R01AI037312-09
Application #
6510579
Study Section
Special Emphasis Panel (ZRG1-VACC (01))
Program Officer
Baker, Phillip J
Project Start
1994-09-30
Project End
2004-06-30
Budget Start
2002-07-01
Budget End
2003-06-30
Support Year
9
Fiscal Year
2002
Total Cost
$431,809
Indirect Cost
Name
University of California Los Angeles
Department
Microbiology/Immun/Virology
Type
Schools of Medicine
DUNS #
119132785
City
Los Angeles
State
CA
Country
United States
Zip Code
90095
Crother, Timothy R; Champion, Cheryl I; Whitelegge, Julian P et al. (2004) Temporal analysis of the antigenic composition of Borrelia burgdorferi during infection in rabbit skin. Infect Immun 72:5063-72
Crother, Timothy R; Champion, Cheryl I; Wu, Xiao-Yang et al. (2003) Antigenic composition of Borrelia burgdorferi during infection of SCID mice. Infect Immun 71:3419-28
Shang, E S; Wu, X Y; Lovett, M A et al. (2001) Homologous and heterologous Borrelia burgdorferi challenge of infection-derived immune rabbits using host-adapted organisms. Infect Immun 69:593-8
Chong-Cerrillo, C; Shang, E S; Blanco, D R et al. (2001) Immunohistochemical analysis of Lyme disease in the skin of naive and infection-immune rabbits following challenge. Infect Immun 69:4094-102
Exner, M M; Wu, X; Blanco, D R et al. (2000) Protection elicited by native outer membrane protein Oms66 (p66) against host-adapted Borrelia burgdorferi: conformational nature of bactericidal epitopes. Infect Immun 68:2647-54
Shang, E S; Champion, C I; Wu, X Y et al. (2000) Comparison of protection in rabbits against host-adapted and cultivated Borrelia burgdorferi following infection-derived immunity or immunization with outer membrane vesicles or outer surface protein A. Infect Immun 68:4189-99
Blanco, D R; Whitelegge, J P; Miller, J N et al. (1999) Demonstration by mass spectrometry that purified native Treponema pallidum rare outer membrane protein 1 (Tromp1) has a cleaved signal peptide. J Bacteriol 181:5094-8
Zhang, H H; Blanco, D R; Exner, M M et al. (1999) Renaturation of recombinant Treponema pallidum rare outer membrane protein 1 into a trimeric, hydrophobic, and porin-active conformation. J Bacteriol 181:7168-75
Blanco, D R; Champion, C I; Lewinski, M A et al. (1999) Immunization with Treponema pallidum outer membrane vesicles induces high-titer complement-dependent treponemicidal activity and aggregation of T. pallidum rare outer membrane proteins (TROMPs). J Immunol 163:2741-6
Shang, E S; Skare, J T; Exner, M M et al. (1998) Isolation and characterization of the outer membrane of Borrelia hermsii. Infect Immun 66:1082-91

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