Extensive analysis of BoLA-I haplotypes and their peptide binding specificities in key T. parva vaccine target populations in endemic areas: Towards rational vaccine development against a major pathogen of cattle

• Applicant: Dr. Isaiah Otieno Obara, Ph.D.
• Subject Area: Veterinary Medical Science
• Term: since 2021
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 460332935

An acute and often fatal lymphocytic tumour-like disease of cattle (East Coast fever, ECF), resulting from immortalization of bovine lymphocytes by the apicomplexan parasite Theileria parva, kills an estimated 1 million cattle annually. Regular and intensive use of acaricides for tick vector control is increasingly less sustainable and chemotherapy is expensive and its effectiveness is dependent on early diagnosis. A live-parasite infection and treatment (ITM) immunisation procedure exists, but several logistical and policy issues have constrained its widespread adoption nearly fifty years after its invention. Development of efficacious and affordable ‘second generation’ subunit vaccines remains a desirable option. Immune control of T. parva is mediated by BoLA-I restricted CD8+ T cells specific for schizont-infected lymphocytes and it has become increasingly evident that individual hosts of different BoLA-I genotypes generally respond to different sets of T. parva epitopes, often in different proteins. A key obstacle to rational development of subunit vaccines is the paucity of information on the prevalence and peptide binding preferences of BoLA-I haplotypes in major vaccine target populations. To date, a limited number of vaccine target cattle populations (largely Holsteins), with a very limited range of BoLA-I alleles, have been examined for antigenic specificity of T. parva– specific CD8+ T cells. However, the Holstein CD8+ T cell targets are not recognised by immune bovine CD8+ T cells from key vaccine target African taurine (Ankole) and indicine (Zebu) cattle. Since BoLA-I haplotypes have yet to be analyzed in detail in these native cattle, the major significance of the first part of the proposal is that it will represent the first extensive analysis of BoLA-I of African cattle, specifically the Ankole and Zebu ‘breeds’. The anticipated outcomes from this component of the research include (i) determination of the most prevalent BoLA-I restriction elements and (ii) haplotype characterization of transcribed Ankole and Zebu BoLA-I genes. In order to generate knowledge needed to underpin rational development of multivalent vaccines that can potentially induce a broadly protective response, I will obtain concurrent data on the peptide binding specificities of a suite of Ankole and Zebu BoLA-I haplotypes and demonstrate whether different T. parva antigens are presented in these major vaccine target populations. This will be addressed by contrasting Ankole and Zebu BoLA-I immunopeptidomes (the repertoire of naturally processed and presented peptides), defined by de novo sequencing of the ensemble of BoLA-I eluted peptides. Further, I intend to maximise the value of the immunopeptidomics approach and the data it creates (self-ligands and pathogen peptides) to decipher the rules underlying MHC antigen presentation to train and improve the machine learning neural network algorithm for predicting BoLA-I peptide presentation.

• DFG Programme: Research Grants