THEILERIA PARVA: IMMUNOPATHOLOGY, CORRELATES OF PROTECTION, AND VACCINE DEVELOPMENT

Lindsay Michelle Fry

East Coast Fever (ECF), caused by the apicomplexan parasite, Theileria parva, kills over a million cattle each year in sub-Saharan Africa. Cattle that develop ECF succumb to respiratory failure-induced pulmonary edema; however, the immunopathogenesis of these lesions is poorly understood. While Cape buffalo and cattle herds raised in T. parva endemic areas seem to develop innate resistance to disease and experience a low mortality rate, cattle herds newly introduced to regions with T. parva often experience up to a 90% mortality rate. These findings led us to hypothesize that ECF results from immune dysregulation during acute infection in naïve cattle. To test this hypothesis, we compared antemortem clinical pathology data, necropsy findings, and histopathology results from twenty African Boran calves and five Holstein calves infected with a lethal dose of T. parva. Infected cattle developed severe vasculitis of medium to large caliber vessels within the lungs and lymphoid organs. Immunohistochemical studies revealed that intralesional macrophages were positive for the pro-inflammatory cytokine, IL-17, and expressed the marker of alternative activation, CD163. These findings, coupled with the antemortem clinical pathology results, suggest that ECF is a form of macrophage activation syndrome (MAS), an often-fatal form of immune dysregulation observed in many infectious diseases and neoplasia. In ECF, parasite-driven lymphoproliferation likely leads to secondary systemic macrophage activation syndrome, vasculitis, pulmonary edema, respiratory failure and death. These findings are discussed in Chapter 1. Following our discovery of the complexity of the immune response in acute T. parva, we began work to better characterize responding leukocyte populations and to define cellular phenotypes associated with both protection and harm in T. parva. Although cytotoxic CD8+ T-cell responses specific for T. parva-infected cells correlate well with protection from T. parva challenge, other features of protective and detrimental immune responses have not yet been elucidated. To fill this gap, we developed flow-cytometric assays to assess cytotoxicity and cytokine production in bovine leukocytes. These assays enable concurrent, multi-parameter assessment of responding leukocytes, and will greatly enhance our understanding of the immune response to T. parva. The development and optimization of these assays is described in Chapter 2

THEILERIA PARVA: IMMUNOPATHOLOGY, CORRELATES OF PROTECTION, AND VACCINE DEVELOPMENT

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