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Generation of mono-allelic BoLA-DRB3 bovine cell lines, immunopeptidomic characterization, and development of NetBoLAIIpan to advance CD4+ T cell epitope mapping and vaccine development

Grant number: 23/14049-3
Support Opportunities:Scholarships abroad - Research Internship - Doctorate
Effective date (Start): March 01, 2024
Effective date (End): August 31, 2024
Field of knowledge:Biological Sciences - Parasitology
Principal Investigator:Beatriz Rossetti Ferreira
Grantee:Alexsander de Moraes
Supervisor: Timothy Connelley
Host Institution: Escola de Enfermagem de Ribeirão Preto (EERP). Universidade de São Paulo (USP). Ribeirão Preto , SP, Brazil
Research place: University of Edinburgh, Scotland  
Associated to the scholarship:22/07400-3 - Development of multi-antigenic vaccine candidates against Rhipicephalus microplus ticks, evaluation of their efficacy and the induced immune response in bovines, BP.DR

Abstract

Cattle production is a significant component in the global livestock industry due to its contribution to both meat and dairy production. Rhipicephalus microplus, the cattle tick, inflicts substantial economic losses on the cattle industry in many tropical and sub-tropical areas of the globe. Current control methods for R. microplus are reliant on acaracides and other chemoprophylactic/therapeutic approaches, which are being degraded through increasing resistance. As a complex parasite, sustainable vaccine control is challenging since it requires several functional classes of antigens. Our research group demonstrated that a vaccine formulation comprising nine salivary antigens was 75% effective in protecting susceptible cattle against R. microplus infestations. We are currently finishing the identification of B cell epitopes within these protective vaccine antigens, which will be employed in developing a novel, single-molecule chimeric anti-tick vaccine for commercialisation. However, it is well-established that for effective antibody responses against pathogens epitopes must be presented by B cell Major Histocompatibility Complex (MHC) II molecules to CD4+ 'helper' T cells to recruit the support required for B cell activation and maturation. In this context, our group has actively worked on the characterisation of MHC-II presented epitopes using immunopeptidomics, which has significantly improved the development and accuracy of MHC-binding prediction algorithms and resulted in generation of the cattle-specific Bovine Leukocyte Antigen (BoLA)-DR ligand prediction tool, NetBoLAIIpan. Such in silico tools can accelerate the rational selection of antigens and epitopes for vaccine development, especially for pathogens, such as ticks, with large proteomes. However, there is an urgent need to expand this prediction tool for broader coverage of cattle populations of interest, such as the Brazilian commercial cattle population; also, the cell models previously used were not optimised and could not be transferred to our laboratory in Brazil due to biosafety limitations, so the development of pathogen-free models represents an alternative to continue our efforts to expand the MHC-II epitope database and anti-tick research capacity in Brazil. To address these challenges, this project aims to generate mono-allelic cell lines expressing BoLA-DRB3 alleles prevalent in the Brazilian commercial cattle such that ~95% coverage is achieved. A well-known BoLA-DRB3 allele will be used as a model for optimising plasmid or lentivirus-mediated DRB3 gene delivery and protein expression on the surface bovine-derived BoLA-null cell lines recently developed by our group. Subsequently, immunopeptidomics and BoLA-DRB3 binding motif analyses will be carried out, and the generated datasets will be compared with the one currently included in the NetBoLAIIpan tool database. Once the protocol for gene delivery is standardised and the motif datasets are validated, the full-length sequences of BoLA-DRB3 prevalent in Brazilian commercial cattle will be characterised and expressed on the bovine-derived BoLA-null cell lines. Finally, the immunopeptidomics analyses and novel motifs datasets will be produced to update the NetBoLAIIpan tool. As a prospective outcome, we will employ the tool in epitope discovery to facilitate antigen selection and the development of epitope-based vaccines against R. microplus, thereby complementing the B cell epitope mapping data.

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