Lyme borreliosis is a prevalent vector-borne disease in the United States, Europe, and parts of Asia, caused by the bacterial pathogen Borrelia burgdorferi. The infection can be difficult to diagnose, and a human vaccine is currently unavailable. The application will study how BBA57 - a unique borrelial gene product and newly identified virulence determinant of unknown function - contributes to multiple aspects of microbial infectivity and pathogenesis and also assess its efficacy in generating protective host immunity against infection. Although many bacterial pathogens have evolved measures to limit host microbicidal responses, relatively little is known about how B. burgdorferi evade innate immunity as they transmit to mammalian hosts. Based on our published and new preliminary data, we hypothesize that BBA57, an in-vivo induced, surface-exposed outer membrane protein, facilitates spirochete defense against specific host innate immune responses and that the antigen induces production of neutrophil-recruiting chemokines in joint cells, which triggers arthritis. Upon successful completion of the proposed work, we will be able to demonstrate that BBA57 represents, to the best of our knowledge, the first example of a B. burgdorferi protein that confers resistance to specific antimicrobial peptides (AMPs), thereby promoting establishment of early B. burgdorferi infection in murine hosts. We have three major goals. First, we will examine how BBA57 contributes to spirochete AMP resistance during early infection. Second, we will identify the joint cell type(s) that are responsible for BBA57-mediated chemokine responses critical for arthritis. Finally, as BBA57 is also dramatically produced in ticks, we will explore the role of the protein in perpetuating the vector phases of the borrelial lfe cycle, including tick-to-mouse transmission, and based on our preliminary immunization data, we will assess its potential as a new candidate antigen for generation of protective host immunity. In sum, these studies will contribute to better understanding the infectivity and pathogenesis of B. burgdorferi and help in the development of novel preventive and therapeutic measures to combat infection.

Public Health Relevance

Lyme disease is a prevalent infection caused by the tick-borne bacterium Borrelia burgdorferi. We propose to study how one B. burgdorferi gene product, BBA57, supports pathogen persistence in the host and in the vector and contributes to microbial pathogenesis. We also plan to assess the ability of recombinant BBA57 to 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 #
5R01AI116620-03
Application #
9201299
Study Section
Host Interactions with Bacterial Pathogens Study Section (HIBP)
Program Officer
Ilias, Maliha R
Project Start
2015-02-01
Project End
2020-01-31
Budget Start
2017-02-01
Budget End
2018-01-31
Support Year
3
Fiscal Year
2017
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
Marques, Adriana R; Yang, Xiuli; Smith, Alexis A et al. (2017) Citrate Anticoagulant Improves the Sensitivity of Borreliella (Borrelia) burgdorferi Plasma Culture. J Clin Microbiol 55:3297-3299
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
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