Location: Infectious Bacterial Diseases Research
Project Number: 5030-32000-234-000-D
Project Type: In-House Appropriated
Start Date: Oct 7, 2021
End Date: Oct 6, 2026
Objective 1: Develop rationally-designed vaccines, including recombinants, that prevent disease or mitigate disease spread with an emphasis on platforms that allow for extended antigen release and remote delivery for cattle and elk. Subobjective 1A: Assess the potential of polyanhydride polymers as extended release vaccine platform using killed bacterial preparations to generate cell-mediated immune responses against Brucella in cattle and elk. Subobjective 1B: Evaluate immunogenicity/efficacy of a new recombinant vaccine in elk. Subobjective 1C: Develop new DIVA vaccine strains with targeted mutations using CRISPR. Objective 2: Improve current diagnostic tests for brucellosis that differentiate between Brucella species and can be used in multiple livestock and wildlife species. Subobjective 2A: Characterize sensitivity and specificity of diagnostic tests using synthetic Brucella antigens. Subobjective 2B: Identify new Brucella epitopes recognized by humoral responses of B. suis infected animals using phage library expression. Objective 3: Using transcriptomic approaches, define the immunopathogenesis of brucellosis at the tissue and cellular level by analyzing gene expression of peripheral immune responses and local immune responses to inform vaccine and therapeutic development. Subobjective 3A: Using a transposon generated mutant library of Brucella abortus, characterize how bacterial populations are limited during in vivo infection and identify bacterial genes critical for establishing infection in cattle. Subobjective 3B: Using a transposon-generated mutant library of Brucella abortus, characterize how pregnancy influences diversity of bacterial populations during in vivo infection in cattle. Subobjective 3C: Characterize the gene expression profiles of the peripheral immune response to Brucella in cattle, bison, and elk to determine species-specific differences in response to vaccination.
The long-term goals of this project are to facilitate the completion of brucellosis eradication programs in domestic livestock, and prevent reintroduction of brucellosis into livestock from wildlife reservoirs. Specifically, fundamental knowledge on Brucella pathogenesis will be gained, efficacious vaccination systems will be identified, and sensitive and specific diagnostic tools will be developed to aid eradication programs. Immunogenicity of vaccination strategies in targeted hosts (cattle, bison, elk, and swine), including novel vaccine platforms, will be evaluated in targeted species and efficacy characterized by experimental challenge. In addition, the project will try to improve the standard experimental challenge model for elk to better replicate the clinical effects of brucellosis under field conditions. By simultaneously characterizing the in vivo transcriptome of B. abortus and natural host during infection, we will develop knowledge of molecular mechanisms involved in regulation of host responses to infection, and genes expressed by the pathogen under in vivo conditions. This basic knowledge will identify future targets for development of new vaccines, diagnostics, immunomodulation, and possibly therapeutics. New diagnostics will be developed and analyzed for their ability to detect brucellosis in swine and cattle, and may allow differentiation of which Brucella spp. is associated with infection. The research will help resolve the risk of re-infection of domestic livestock from wildlife reservoirs of brucellosis, protect the financial investment that has been made in the U.S. brucellosis eradication program, and provide public health benefits by reducing the risk of zoonotic infection.