Gene gun DNA immunization of cattle induces humoral and CD4 T-cell-mediated immune responses against the Theileria parva polymorphic immunodominant molecule

Lindsay M Fry,Reginaldo G Bastos,Brad C Stone,Laura B Williams,Donald P Knowles,Sean C Murphy

doi:10.1016/j.vaccine.2019.02.009

Abstract

Theileria parva kills over one million cattle annually in sub-Saharan Africa. Parasite genetic complexity, cellular response immunodominance, and bovine MHC diversity have precluded traditional vaccine development. One potential solution is gene gun (GG) immunization, which enables simultaneous administration of one or more DNA-encoded antigens. Although promising in murine, porcine, and human vaccination trials, bovine GG immunization studies are limited. We utilized the model T. parva antigen, polymorphic immunodominant molecule (PIM) to test bovine GG immunization. GG immunization using a mammalian codon optimized PIM sequence elicited significant anti-PIM antibody and cell-mediated responses in 7/8 steers, but there was no difference between immunized and control animals following T. parva challenge. The results suggest immunization with PIM, as delivered here, is insufficient to protect cattle from T. parva. Nonetheless, the robust immune responses elicited against this model antigen suggest GG immunization is a promising vaccine platform for T. parva and other bovine pathogens.

Highlights

The tick-borne, apicomplexan parasite Theileria parva kills over one million cattle annually in sub-Saharan Africa [1]
Mortality rates are highest in European cattle breeds imported for higher meat and milk yields, and most losses are Abbreviations: BAEC, bovine aortic endothelial cells; BoLA, bovine leukocyte antigen; CBC, complete blood count; CO, codon-optimized; East Coast Fever (ECF), east coast fever; enzyme-linked immunosorbent assay (ELISA), enzyme linked immunosorbent assay; GG, gene gun; HEK, human embryonic kidney cells; IFNc, interferon gamma; ITM, infection and treatment method; MHC, major histocompatibility complex; PIM, polymorphic immunodominant molecule
Widespread adoption of ITMimmunization in the region is severely limited by its prohibitive cost, requirement for liquid nitrogen storage, necessity of antibiotic co-treatment, and induction of a T. parva carrier state in immunized cattle, resulting in possible ITM-strain transfer to new areas [1,8]

Summary

Introduction

The tick-borne, apicomplexan parasite Theileria parva kills over one million cattle annually in sub-Saharan Africa [1]. Infection results in a clinical syndrome known as East Coast Fever (ECF), characterized by pyrexia, lymphadenopathy, and respiratory failure [2]. Mortality rates are highest in European cattle breeds imported for higher meat and milk yields, and most losses are Abbreviations: BAEC, bovine aortic endothelial cells; BoLA, bovine leukocyte antigen; CBC, complete blood count; CO, codon-optimized; ECF, east coast fever; ELISA, enzyme linked immunosorbent assay; GG, gene gun; HEK, human embryonic kidney cells; IFNc, interferon gamma; ITM, infection and treatment method; MHC, major histocompatibility complex; PIM, polymorphic immunodominant molecule. Protective immunity is elicited by sub-lethal natural infection and by the infection and treatment method (ITM), whereby cattle are infected with cryopreserved, T. parva-infected tick stabilate and co-treated with oxytetracycline [1].

Methods

Results

Conclusion