Lyme borreliosis is a prevalent vector-borne disease in the United States, Europe, and parts of Asia, caused the infection with the bacterial pathogen Borrelia burgdorferi. Despite several decades of intense studies, many fundamental aspects of pathogen biology and infection remain largely unknown. B. burgdorferi infection can be difficult to diagnose, and a vaccine to prevent disease in humans is currently unavailable. The application will study how a select set of unique borrelial gene-products BB0323, BBA52 and BBA57 that play important roles in the spirochete infection cycle, contribute to specific aspects of microbial biology and pathogenesis and also assess their potential utility as Lyme disease vaccines. We have four major goals. First, we will examine how a critical virulence determinant of B. burgdorferi, BB0323 undergoes two-step proteolytic processing that ultimately produce distinct N- and C-terminal polypeptides, which play specific roles in cell fission and infectivity. Second, we have discovered that BBA52 is critical for pathogen transmission from ticks to mice and that the protein binds to a receptor in ticks. We propose to study a potential function of BBA52 in vector-pathogen interaction and its role in B. burgdorferi persistence and transmission through ticks. Third, we show that BBA57, a borrelial gene-product important for early spirochete infection in mice, is a major trigger of Lyme arthritis. Our studies will dissect detail molecular and cellular mechanisms of how BBA57 triggers host inflammatory responses and also facilitates spirochete infection. Finally, the proposed study will explore the identification f new vaccine candidates as well as New castle disease virus (NDV) vector-based immunization strategies against Lyme disease. As NDV appears to be safe in humans and is currently in use for therapeutic treatment of cancer patients, the proposed study will establish a foundation for it utility as a possible vaccine vector against human Lyme disease. In sum, these studies will contribute to the understanding of the intriguing biology and infectivity of B. burgdorferi and hel develop novel preventive and therapeutic measures to combat infection.

Public Health Relevance

Lyme disease is a prevalent infection caused by the tick-borne bacterial pathogen Borrelia burgdorferi. We propose to study how a select set of B. burgdorferi antigens that support pathogen persistence contributes to microbial biology, infection and pathogenesis. We also propose to identify novel vaccine targets as well immunization platforms that induce protective host immunity against B. burgdorferi infection.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Project (R01)
Project #
2R01AI080615-05A1
Application #
8636247
Study Section
Host Interactions with Bacterial Pathogens Study Section (HIBP)
Program Officer
Breen, Joseph J
Project Start
2009-07-01
Project End
2018-07-31
Budget Start
2014-08-26
Budget End
2015-07-31
Support Year
5
Fiscal Year
2014
Total Cost
$380,000
Indirect Cost
$130,000
Name
University of Maryland College Park
Department
Veterinary Sciences
Type
Schools of Earth Sciences/Natur
DUNS #
790934285
City
College Park
State
MD
Country
United States
Zip Code
20742
Zhang, Kai; Bian, Jiang; Deng, Yijie et al. (2016) Lyme disease spirochaete Borrelia burgdorferi does not require thiamin. Nat Microbiol 2:16213
Ye, Meiping; Sharma, Kavita; Thakur, Meghna et al. (2016) HtrA, a Temperature- and Stationary Phase-Activated Protease Involved in Maturation of a Key Microbial Virulence Determinant, Facilitates Borrelia burgdorferi Infection in Mammalian Hosts. Infect Immun 84:2372-81
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Smith, Alexis A; Navasa, Nicolas; Yang, Xiuli et al. (2016) Cross-Species Interferon Signaling Boosts Microbicidal Activity within the Tick Vector. Cell Host Microbe 20:91-8
Yang, Xiuli; Lin, Yi-Pin; Heselpoth, Ryan D et al. (2016) Middle region of the Borrelia burgdorferi surface-located protein 1 (Lmp1) interacts with host chondroitin-6-sulfate and independently facilitates infection. Cell Microbiol 18:97-110
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Earnhart, Christopher G; Rhodes, DeLacy V L; Smith, Alexis A et al. (2014) Assessment of the potential contribution of the highly conserved C-terminal motif (C10) of Borrelia burgdorferi outer surface protein C in transmission and infectivity. Pathog Dis 70:176-84
Yang, Xiuli; Smith, Alexis A; Williams, Mark S et al. (2014) A dityrosine network mediated by dual oxidase and peroxidase influences the persistence of Lyme disease pathogens within the vector. J Biol Chem 289:12813-22
Lin, Yi-Pin; Benoit, Vivian; Yang, Xiuli et al. (2014) Strain-specific variation of the decorin-binding adhesin DbpA influences the tissue tropism of the lyme disease spirochete. PLoS Pathog 10:e1004238

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