The overall objective of this project is to understand the pathogenesis of Lyme borreliosis, using a mouse model. This project will focus on mechanisms of antibody-mediated disease remission and mechanisms by which spirochetes evade immune clearance. Immune serum from persistently infected mice contains three measurable functional effects: protective, disease-resolving, and spirochete-reducing effects. Two lipoproteins are reactive with antibody within immune serum: decorin binding protein A (DbpA) and arthritis-related protein (Arp). Antiserum against recombinant DbpA is protective and disease-resolving, whereas Arp antiserum is disease-resolving, but not protective. Neither antiserum reduces overall spirochete numbers in tissues. These antisera induce disease remission by eliminating spirochetes from specific tissues, including synovium and heart base, but spirochetes evade the effects of immune serum or these antisera by sequestration within collagenous tissue. Antibody-mediated disease remission will be examined, using laser capture microdissection, quantitative real-time polymerase chain reaction for spirochetal DNA and RNA, and immunohistochemistry. The specific roles of DbpA and Arp in disease evolution, disease remission and persistence in collagen will be investigated using genetic null and complemented mutants of Borrelia burgdorferi. The functional state of spirochetes during persistent infection will be explored in order to determine the specific antigen-antibody interactions involved in maintaining disease quiescence and sequestration of spirochetes in collagen, and to determine if the persistent state is either static or dynamic, using parabiotic mice infected with co-isogenic strains of spirochetes. These studies are highly relevant to understanding how B. burgdorferi persists in the immunologically responsive host, and how the host maintains the host-parasite equilibrium. Lyme borreliosis is the most common vector-borne disease in the U.S., with significant morbidity, and its prevalence and geographic distribution are rising. These studies are needed to develop better strategies for effective management of patients with persistent infections. Relevance: Pathogen persistence and evasion of host immunity are highly relevant issues for all chronic infectious diseases, but Lyme borreliosis in particular. The proposed studies will incisively investigate the mechanisms of Borrelia burgdorferi persistence, which will help lead to more effective treatment.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Project (R01)
Project #
5R01AI026815-24
Application #
8197151
Study Section
Host Interactions with Bacterial Pathogens Study Section (HIBP)
Program Officer
Breen, Joseph J
Project Start
1988-07-01
Project End
2012-11-30
Budget Start
2011-12-01
Budget End
2012-11-30
Support Year
24
Fiscal Year
2012
Total Cost
$372,438
Indirect Cost
$127,413
Name
University of California Davis
Department
Veterinary Sciences
Type
Schools of Veterinary Medicine
DUNS #
047120084
City
Davis
State
CA
Country
United States
Zip Code
95618
Hodzic, Emir; Imai, Denise; Feng, Sunlian et al. (2014) Resurgence of persisting non-cultivable Borrelia burgdorferi following antibiotic treatment in mice. PLoS One 9:e86907
Hodzic, Emir; Feng, Sunlian; Barthold, Stephen W (2013) Assessment of transcriptional activity of Borrelia burgdorferi and host cytokine genes during early and late infection in a mouse model. Vector Borne Zoonotic Dis 13:694-711
Imai, Denise M; Samuels, D Scott; Feng, Sunlian et al. (2013) The early dissemination defect attributed to disruption of decorin-binding proteins is abolished in chronic murine Lyme borreliosis. Infect Immun 81:1663-73
Imai, Denise M; Feng, Sunlian; Hodzic, Emir et al. (2013) Dynamics of connective-tissue localization during chronic Borrelia burgdorferi infection. Lab Invest 93:900-10
Imai, Denise; Holden, Kevin; Velazquez, Eric M et al. (2013) Influence of arthritis-related protein (BBF01) on infectivity of Borrelia burgdorferi B31. BMC Microbiol 13:100
Embers, Monica E; Barthold, Stephen W; Borda, Juan T et al. (2012) Persistence of Borrelia burgdorferi in rhesus macaques following antibiotic treatment of disseminated infection. PLoS One 7:e29914
Imai, D M; Barr, B C; Daft, B et al. (2011) Lyme neuroborreliosis in 2 horses. Vet Pathol 48:1151-7
Tunev, Stefan S; Hastey, Christine J; Hodzic, Emir et al. (2011) Lymphoadenopathy during lyme borreliosis is caused by spirochete migration-induced specific B cell activation. PLoS Pathog 7:e1002066
Barthold, Stephen W; Hodzic, Emir; Imai, Denise M et al. (2010) Ineffectiveness of tigecycline against persistent Borrelia burgdorferi. Antimicrob Agents Chemother 54:643-51
Hodzic, Emir; Feng, Sunlian; Holden, Kevin et al. (2008) Persistence of Borrelia burgdorferi following antibiotic treatment in mice. Antimicrob Agents Chemother 52:1728-36

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